Easy To Use Patents Search & Patent Lawyer Directory

At Patents you can conduct a Patent Search, File a Patent Application, find a Patent Attorney, or search available technology through our Patent Exchange. Patents are available using simple keyword or date criteria. If you are looking to hire a patent attorney, you've come to the right place. Protect your idea and hire a patent lawyer.

The use of substituted amides for modulating the activity of
11.beta.-hydroxysteroid dehydrogenase type 1 (11.beta.HSD1) and the use
of these compounds as pharmaceutical compositions, are described. Also a
novel class of substituted amides, their use in therapy, pharmaceutical
compositions comprising the compounds, as well as their use in the
manufacture of medicaments are described. The present compounds are
modulators and more specifically inhibitors of the activity of
11.beta.HSD1 and may be useful in the treatment, prevention and/or
prophylaxis of a range of medical disorders where a decreased
intracellular concentration of active glucocorticoid is desirable.

1. A method of modulating of the activity of 11.beta.HSD1, or inhibiting
11.beta.HSD1, comprising administering to a patient in need of such
method a therapeutically effective amount of a substituted amide, a
prodrug thereof, or a salt thereof with a pharmaceutically acceptable
acid or base, or optical isomer or mixture of optical isomers, racemic
mixture or tautomeric forms thereof.

2. A method for the treatment, prevention and/or prophylaxis of any
disorder and disease where it is desirable to modulate the activity of
11.beta.HSD1, or inhibit 11.beta.HSD1, comprising administering to a
patient in need of such method a therapeutically effective amount of a
substituted amide, a prodrug thereof, or a salt thereof with a
pharmaceutically acceptable acid or base, or optical isomer or mixture of
optical isomers, racemic mixture or any tautomeric forms thereof.

4. The method according to claim 3, wherein the substituted amide or a
prodrug thereof is of formula (I) wherein R.sup.1 is
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl or
hetarylC.sub.1-C.sub.6alkyl, wherein the cycloalkyl, hetcycloalkyl,
alkyl, arylalkyl and hetarylalkyl groups independently are optionally
substituted with one or more of R.sup.4; R.sup.2 is hydrogen,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl wherein the alkyl, aryl
and cycloalkyl groups independently are optionally substituted with one
or more of R.sup.5; or R.sup.1 and R.sup.2 are together with the nitrogen
to which they are attached, are forming a saturated or partially
saturated cyclic, bicyclic or tricyclic ring system containing from 4 to
10 carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being substituted
with at least one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or arylC.sub.1-6alkylcarboxy
wherein the alkyl and aryl groups independently are optionally
substituted with one or more of R.sup.14; R.sup.3 is
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkenyl, C.sub.1-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, aryl-R.sup.6--C.sub.1-C.sub.6alkyl,
hetaryl-R.sup.6--C.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl wherein the alkyl,
cycloalkyl, hetcycloalkyl, alkenyl, alkynyl, aryl and hetaryl groups
independently are optionally substituted with one or more of R.sup.7;
R.sup.4 and R.sup.5 independently are hydrogen, hydroxy, oxo, cyano,
halo, methylendioxo, NR.sup.8R.sup.9, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.6alkyloxy, trihalomethyl, trihalomethyloxy,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkenyl, aryl, hetaryl, hetarylSO.sub.n,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylcarbonyl,
hetarylC.sub.1-C.sub.6alkyl-carbonyl, C.sub.1-C.sub.6alkylSO.sub.n,
C.sub.1-C.sub.6alkyl-carboxy, arylcarboxy, hetarylcarboxy,
arylC.sub.1-C.sub.6alkylcarboxy or hetarylC.sub.1-C.sub.6alkylcarboxy
wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups
independently are optionally substituted with one or more of R.sup.15;
R.sup.6 is oxygen, sulphur, SO.sub.n, NR.sup.16; R.sup.7 is hydrogen,
halo, hydroxyl, cyano, nitro, COOR.sup.7, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl, methylendioxo,
trihalomethyl, trihalomethyloxy, aryl, arylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
aryloxy, aryloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, hetaryloxy, hetarylC.sub.1-C.sub.6alkyloxy,
hetaryloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, NR.sup.8R.sup.9,
SO.sub.2NR.sup.8R.sup.9, NR.sup.4R.sup.5carbonylalkyl,
arylcarbonylNR.sup.8, arylthio, hetarylthio, arylSO.sub.n,
hetarylSO.sub.n, arylSO.sub.mNR.sup.8, arylthioC.sub.1-C.sub.6alkyl,
hetarylthioC.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkylR.sup.6C.sub.1-C.sub.6alkyl; wherein the aryl and
hetaryl groups independently are optionally substituted with one or more
R.sup.10; R.sup.8 and R.sup.9 independently are hydrogen,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl or
hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, aryl and hetaryl groups
independently are optionally substituted with one or more of R.sup.11; or
R.sup.8 and R.sup.9 together with the nitrogen to which they are
attached, are forming a saturated or partially saturated cyclic, bicyclic
or tricyclic ring system containing from 4 to 10 carbon atoms and from 0
to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the
ring system optionally being substituted with at least one
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy, hetarylcarboxy,
arylC.sub.1-C.sub.6alkyl-carboxy or hetarylC.sub.1-C.sub.6alkylcarboxy;
R.sup.10 and R.sup.11 independently are hydrogen, hydroxy, oxo, halo,
cyano, nitro, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy,
NR.sup.12R.sup.13, methylendioxo, trihalomethyl or trihalomethyloxy;
R.sup.12 and R.sup.13 independently are hydrogen, C.sub.1-C.sub.8alkyl or
arylC.sub.1-C.sub.6alkyl; R.sup.14 is hydrogen, halo, hydroxy, oxo,
nitro, cyano, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy or aryloxy;
R.sup.15 is hydrogen, halo, hydroxy, oxo, nitro, cyano or COOR.sup.17;
R.sup.16 is hydrogen, C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, aryloxyC.sub.1-C.sub.6alkyl,
hetaryloxyC.sub.1-C.sub.6alkyl, arylthioC.sub.1-C.sub.6alkyl or
hetarylthioC.sub.1-C.sub.6alkyl; wherein the alkyl, cycloalkyl,
hetcycloalkyl, aryl and hetaryl groups independently are optionally
substituted with one or more of R.sup.10; R.sup.17 is hydrogen,
C.sub.1-C.sub.8alkyl, aryl or arylC.sub.1-C.sub.6alkyl; m is 1 or 2; n is
0, 1 or 2; or a salt thereof with a pharmaceutically acceptable acid or
base, or optical isomer or mixture of optical isomers, racemic mixture,
or tautomeric forms thereof.

5. The method according to claim 3, wherein R.sup.1 is
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl, wherein the
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.4.

6. The method according to claim 3, wherein R.sup.2 is hydrogen or
C.sub.1-C.sub.8alkyl, wherein the alkyl group is optionally substituted
with one or more of R.sup.5.

7. The method according to claim 3, wherein R.sup.1 and R.sup.2 together
with the nitrogen to which they are attached, are forming a saturated or
partially saturated cyclic, bicyclic or tricyclic ring system containing
from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected
from nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.14.

8. The method according to claim 3, wherein R.sup.3 is
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
aryl-R.sup.6--C.sub.1-C.sub.6alkyl, hetaryl-R.sup.6--C.sub.1-C.sub.6alkyl
or arylC.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl wherein the
alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently
are optionally substituted with one or more of R.sup.7.

9. The method according to claim 3, wherein R.sup.4 and R.sup.5
independently are hydrogen, hydroxy, oxo, halo, C.sub.1-C.sub.8alkyl,
wherein the alkyl group is optionally substituted with one or more of
R.sup.15.

12. The method according to claim 3, wherein R.sup.8 and R.sup.9 together
with the nitrogen to which they are attached, are forming a saturated or
partially saturated cyclic, bicyclic or tricyclic ring system containing
from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected
from nitrogen, oxygen or sulfur, the ring system optionally being
substituted with at least one halo, cyano, C.sub.1-C.sub.8alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy, hetarylcarboxy,
arylC.sub.1-C.sub.6alkylcarboxy or hetarylC.sub.1-C.sub.6alkylcarboxy.

13. The method according to claim 3, wherein R.sup.15 is
CONR.sup.8R.sup.9.

14. The method according to claim 3, wherein R.sup.18 is
C.sub.1-C.sub.6alkyl.

16. A pharmaceutical composition comprising a therapeutically effective
amount of a compound according to claim 3, together with one or more
pharmaceutically acceptable carriers or excipients.

17. The pharmaceutical composition according to claim 16, wherein the
pharmaceutical composition is for oral, nasal, buccal, transdermal,
pulmonal or parenteral administration.

18. The pharmaceutical composition according to claim 16, wherein the
pharmaceutical composition is in unit dosage form, comprising from about
0.05 mg to about 2000 mg/day, from about 0.1 mg to about 1000 mg, or from
about 0.5 mg to about 500 mg per day of the compound.

19. A method for the treatment, prevention and/or prophylaxis of
conditions, disorders or diseases wherein a modulation or an inhibition
of the activity of 11.beta.HSD1 is beneficial, the method comprising
administering to a subject in need thereof an effective amount of a
compound according to claim 3.

20. The method according to claim 19, wherein the treatment, prevention
and/or prophylaxis is of any conditions, disorders and diseases that are
influenced by intracellular glucocorticoid levels.

21. The method according to claim 19 or 20, wherein the condition,
disorder or disease is the metabolic syndrome, insulin resistance,
dyslipidemia, hypertension and obesity.

29. A compound according to claim 28, wherein R.sup.1 is
C.sub.3-C.sub.10cycloalkyl or C.sub.3-C.sub.10hetcycloalkyl, wherein the
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.4.

30. A compound according to claim 28, wherein R.sup.2 is hydrogen or
C.sub.1-C.sub.8alkyl.

31. A compound according to claim 28, wherein R.sup.1 and R.sup.2 together
with the nitrogen to which they are attached, are forming a saturated or
partially saturated cyclic, bicyclic or tricyclic ring system containing
from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected
from nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.14.

32. A compound according to claim 28, wherein R.sup.3 is aryl or hetaryl,
wherein the aryl and hetaryl groups independently are optionally
substituted with one or more of R.sup.7.

33. A compound according to claim 28, wherein R.sup.4 and R.sup.5
independently are hydrogen, hydroxy, oxo, halo, C.sub.1-C.sub.8alkyl,
wherein the alkyl group is optionally substituted with one or more of
R.sup.15.

35. A compound according to claim 28, wherein R.sup.8 and R.sup.9 together
with the nitrogen to which they are attached, are forming a saturated or
partially saturated cyclic, bicyclic or tricyclic ring system containing
from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected
from nitrogen, oxygen or sulfur, the ring system optionally being
substituted with at least one halo, cyano, C.sub.1-C.sub.8alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy, hetarylcarboxy,
arylC.sub.1-C.sub.6alkylcarboxy or hetarylC.sub.1-C.sub.6alkylcarboxy.

36. A compound according to claim 28, wherein R.sup.15 is
CONR.sup.8R.sup.9.

37. A compound according to claim 28, wherein R.sup.18 is
C.sub.1-C.sub.6alkyl.

39. A compound of formula (III): wherein R.sup.1 is aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylC.sub.1-C.sub.6alkyl
optionally substituted with one or more of R.sup.6 independently; R.sup.2
is halo, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, trihalomethyl, aryl,
arylC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6-alkylNR.sup.5C.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkylNR.sup.5C.sub.1-C.sub.6alkyl, hetaryl or
hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, alkenyl, alkynyl,
cycloalkyl and aryl groups independently are optionally substituted with
one or more R.sup.7; R.sup.3 is C.sub.1-C.sub.6alkyl optionally
substituted with one or more of R.sup.8; R.sup.4 is
C.sub.6-C.sub.10cycloalkyl, C.sub.6-C.sub.10hetcycloalkyl,
C.sub.6-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl or
C.sub.6-C.sub.10hetcycloalkylC.sub.1-C.sub.6alkyl wherein the alkyl,
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.8; or R.sup.3 and R.sup.4 together
with the nitrogen to which they are attached, are forming a saturated or
partially saturated bicyclic/bridge ring system containing from 7 to 12
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being substituted
with at least one of C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy, wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.9;
R.sup.5 is C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10-cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10hetcycloalkylC.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl wherein the
alkyl, alkenyl, alkynyl, aryl, hetaryl, cycloalkyl and hetcycloalkyl
groups independently are optionally substituted with one or more of
R.sup.9; R.sup.6 and R.sup.7 independently are hydrogen, hydroxy, oxo,
halo, nitro, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6-alkyloxy,
trihalomethyl, trihalomethoxy, NR.sup.10R.sup.11,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6-alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkyloxycarbonyl,
aryloxycarbonyl, arylC.sub.1-C.sub.6alkyloxycarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy; R.sup.8 and R.sup.9 independently are
hydrogen, C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6-alkyl, hydroxy, oxo, cyano, NR.sup.10R.sup.11,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy,
hetaryloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 and R.sup.11 independently are
hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl; or R.sup.10 and R.sup.11
together with the nitrogen to which they are attached, are forming a
saturated or partially saturated cyclic, bicyclic or tricyclic ring
system containing from 4 to 10 carbon atoms and from 0 to 2 additional
heteroatoms selected from nitrogen, oxygen or sulphur, the ring system
optionally being substituted with at least one of C.sub.1-C.sub.8alkyl,
aryl, hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
hydroxy, oxo, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or arylC.sub.1-6-alkylcarboxy;
or a salt thereof with a pharmaceutically acceptable acid or base, or
optical isomer or mixture of optical isomers, racemic mixture, or
tautomeric forms thereof.

41. A compound according to claim 39, wherein R.sup.1 is aryl,
arylC.sub.1-C.sub.6alkyl or hetaryl optionally substituted with one or
more of R.sup.6.

42. A compound according to claim 39, wherein R.sup.2 is
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, trihalomethyl,
arylC.sub.1-C.sub.6alkyl, or hetarylC.sub.1-C.sub.6alkyl wherein the
alkyl, cycloalkyl and aryl groups independently are optionally
substituted with one or more R.sup.7.

43. A compound according to claim 39, wherein R.sup.3 is
C.sub.1-C.sub.6alkyl optionally substituted with one or more of R.sup.8.

44. A compound according to claim 39, wherein R.sup.4 is
C.sub.6-C.sub.10cycloalkyl, or C.sub.6-C.sub.10hetcycloalkyl, wherein the
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.3.

46. A compound according to claim 39, wherein R.sup.8 and R.sup.9
independently are hydrogen, C.sub.1-C.sub.6alkyl, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy or arylC.sub.1-C.sub.6alkyloxy.

47. A compound according to claim 39, wherein R.sup.10 and R.sup.11
independently are hydrogen or C.sub.1-C.sub.8alkyl.

48. A compound according to claim 39, which is
1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide, or a salt thereof with a pharmaceutically
acceptable acid or base, or optical isomer or mixture of optical isomers,
racemic mixture, or tautomeric forms thereof.

49. A compound according to claim 39, selected from the group consisting
of: 1-(4-Chlorophenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide;
[1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-(1,3,3-trimethyl-6-aza-bi-
cyclo[3.2.1]oct-6-yl)-methanone;
[1-(4-Chloro-phenyl)-5-propyl-1H-pyrazol-4-yl]-(1,3,3-trimethyl-6-aza-bic-
yclo[3.2.1]oct-6-yl)-methanone; and
[1-(3,5-Dichloro-phenyl)-5-propyl-1H-pyrazol-4-yl]-(1,3,3-trimethyl-6-aza-
-bicyclo[3.2.1]oct-6-yl)-methanone; or a salt thereof with a
pharmaceutically acceptable acid or base, or optical isomer or mixture of
optical isomers, racemic mixture, or tautomeric forms thereof.

51. A compound of formula (IV): wherein R.sup.1 is hydrogen,
trihalomethyl, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkylthio, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or
hetaralkyl, wherein the alkyl, aryl and hetaryl groups independently are
optionally substituted with one or more of R.sup.8; R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 independently are hydrogen, halo, nitro, cyano,
hydroxy, NR.sup.9R.sup.10, trihalomethyl, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylthio, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetaralkyl, wherein the alkyl, aryl
and hetaryl groups independently are optionally substituted with one or
more of R.sup.8; or R.sup.2 together with R.sup.3 are forming a saturated
or partially saturated cyclic ring system containing from 3 to 6 carbon
atoms and from 0 to 2 additional heteroatoms selected from nitrogen,
oxygen or sulphur, the ring system optionally being substituted with at
least one of C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy; or R.sup.3 together with R.sup.4 are
forming a saturated or partially saturated cyclic ring system containing
from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected
from nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy; or R.sup.4 together with R.sup.5 are
forming a saturated or partially saturated cyclic ring system containing
from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected
from nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy; R.sup.6 is aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl, wherein the alkyl, aryl
and cycloalkyl groups independently are optionally substituted with one
or more of R.sup.11; R.sup.7 is C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl, wherein the alkyl, aryl
and cycloalkyl groups independently are optionally substituted with one
or more of R.sup.11; or R.sup.6 and R.sup.7, together with the nitrogen
to which they are attached, are forming a saturated or partially
saturated cyclic, bicyclic or tricyclic ring system containing from 6 to
10 carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being substituted
with at least one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or arylC.sub.1-6-alkylcarboxy
wherein the alkyl and aryl groups independently are optionally
substituted with one or more of R.sup.8; R.sup.9 and R.sup.10
independently are hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl, wherein the alkyl, aryl
and cycloalkyl groups independently are optionally substituted with one
or more of R.sup.11; or R.sup.9 and R.sup.10, together with the nitrogen
to which they are attached, are forming a saturated or partially
saturated cyclic, bicyclic or tricyclic ring system containing from 4 to
10 carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being substituted
with at least one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6-alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.8;
R.sup.8 and R.sup.11 independently are hydrogen, halo, hydroxy, oxo,
nitro, cyano, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6-alkyloxy or aryloxy;
or a salt thereof with a pharmaceutically acceptable acid or base, or
optical isomer or mixture of optical isomers, racemic mixture, a prodrug
thereof, or tautomeric forms thereof.

52. A compound according to claim 51, wherein R.sup.1 is hydrogen or
C.sub.1-C.sub.6alkyl, wherein the alkyl group is optionally substituted
with one or more of R.sup.8.

53. A compound according to claim 51, wherein R.sup.2, R.sup.3, R.sup.4
and R.sup.5 are hydrogen.

54. A compound according to claim 51, wherein R.sup.6 and R.sup.7,
together with the nitrogen to which they are attached, are forming a
saturated or partially saturated cyclic, bicyclic or tricyclic ring
system containing from 6 to 10 carbon atoms and from 0 to 2 additional
nitrogen or oxygen atoms, the ring system optionally being substituted
with at least one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6-alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.8.

55. A compound according to claim 51, which is:
pyrazolo[1,5-a]pyridin-3-yl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl-
)-methanone; or a salt thereof with a pharmaceutically acceptable acid or
base, or optical isomer or mixture of optical isomers, racemic mixture, a
prodrug thereof, or tautomeric forms thereof.

56. A compound according to claim 51, which is selected from:
(2-Methyl-pyrazolo[1,5-a]pyridin-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2-
.1]oct-6-yl)-methanone; and Pyrazolo[1,5-a]pyridine-3-carboxylic acid
cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically
acceptable acid or base, or optical isomer or mixture of optical isomers,
racemic mixture, or tautomeric forms thereof.

57. A compound of formula (V): wherein R.sup.1 is hydrogen,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6SO.sub.2, arylSO.sub.2, hetarylSO.sub.2,
arylC.sub.1-C.sub.6alkylSO.sub.2 or hetarylC.sub.1-C.sub.6alkylSO.sub.2
optionally substituted with one or more R.sup.8; R.sup.2 and R.sup.5
independently are hydrogen, halo, nitro, cyano, trihalomethyl,
C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or
hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, aryl, arylalkyl, hetaryl
and hetarylalkyl groups independently are substituted with one or more
R.sup.9; and either R.sup.3 is hydrogen; and R.sup.4 is
C(O)NR.sup.7R.sup.8; or R.sup.3 is C(O)NR.sup.7R.sup.8; and R.sup.4 is
hydrogen; R.sup.6 is hydrogen, halo, cyano, trihalomethyl,
NR.sup.12R.sup.13, C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl,
hetaryl or hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, aryl,
arylalkyl, hetaryl and hetarylalkyl groups independently are substituted
with one or more R.sup.9; and R.sup.7 and R.sup.8 independently are
C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the alkyl,
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.10; or R.sup.7 and R.sup.8 together
with the nitrogen to which they are attached, are forming a saturated or
partially saturated bicyclic or tricyclic ring system containing from 6
to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen or oxygen, the ring system optionally being substituted with at
least one of C.sub.1-C.sub.8alkyl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.11;
R.sup.9 is hydrogen, hydroxy, oxo, halo, nitro, cyano,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy, trihalomethyl,
trihalomethoxy, NR.sup.12R.sup.13, C(O)NR.sup.12R.sup.13,
arylC.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 and R.sup.11
independently are hydrogen, halo, oxo, hydroxy, C.sub.1-C.sub.6alkyl,
aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylalkyl; R.sup.12 and
R.sup.13 independently are hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.8alkylcarbonyl, hetarylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl; or R.sup.12 and R.sup.13
together with the nitrogen to which they are attached, are forming a
saturated or partially saturated cyclic, bicyclic or tricyclic ring
system containing from 4 to 10 carbon atoms and from 0 to 2 additional
heteroatoms selected from nitrogen, oxygen or sulphur, the ring system
optionally being substituted with at least one of C.sub.1-C.sub.8alkyl,
aryl, hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
hydroxy, oxo, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy; or a salt thereof with a
pharmaceutically acceptable acid or base, or optical isomer or mixture of
optical isomers, racemic mixture, a prodrug thereof, or tautomeric forms
thereof.

58. A compound according to claim 57, of formula (Va): wherein R.sup.1 is
hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl
or hetarylC.sub.1-C.sub.6alkyl optionally substituted with one or more
R.sup.8; R.sup.2 and R.sup.5 independently are hydrogen, halo, nitro,
cyano, trihalomethyl, C.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylC.sub.1-C.sub.6alkyl wherein
the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups independently
are substituted with one or more R.sup.8; and either R.sup.3 is hydrogen;
and R.sup.4 is C(O)NR.sup.6R.sup.7; or R.sup.3 is C(O)NR.sup.6R.sup.7;
and R.sup.4 is hydrogen; R.sup.6 and R.sup.7 independently are
C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the alkyl,
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.9; or R.sup.6 and R.sup.7 together
with the nitrogen to which they are attached, are forming a saturated or
partially saturated bicyclic or tricyclic ring system containing from 6
to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen or oxygen, the ring system optionally being substituted with at
least one of C.sub.1-C.sub.8alkyl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.10;
R.sup.8 is hydrogen, hydroxy, oxo, halo, nitro, cyano,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy, trihalomethyl,
trihalomethoxy, NR.sup.11R.sup.12, arylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; R.sup.9 and R.sup.10
independently are hydrogen, halo, oxo, hydroxy, C.sub.1-C.sub.6alkyl,
aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylalkyl; R.sup.11 and
R.sup.12 independently are hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyl-carboxyC.sub.1-C.sub.6alkyl; or R.sup.11 and
R.sup.12 together with the nitrogen to which they are attached, are
forming a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur, the
ring system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkyl-carbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy; or a salt thereof with a
pharmaceutically acceptable acid or base, or optical isomer or mixture of
optical isomers, racemic mixture, a prodrug thereof, or tautomeric forms
thereof.

59. A compound according to claim 57, wherein R.sup.1 is hydrogen,
C.sub.1-C.sub.8alkyl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, arylSO.sub.2, hetarylSO.sub.2,
arylC.sub.1-C.sub.6alkylSO.sub.2 or hetarylC.sub.1-C.sub.6alkylSO.sub.2
all of which is optionally substituted with one or more R.sup.8.

60. A compound according to claim 57, wherein R.sup.2 and R.sup.5 are
hydrogen.

61. A compound according to claim 57, wherein R.sup.3 is hydrogen and
R.sup.4 is C(O)NR.sup.7R.sup.8.

62. A compound according to claim 57, wherein R.sup.3 is
C(O)NR.sup.7R.sup.8 and R.sup.4 is hydrogen.

63. A compound according to claim 57, wherein R.sup.6 is hydrogen,
NR.sup.12R.sup.13, C.sub.1-C.sub.6alkyl, aryl or hetaryl wherein the
alkyl, aryl and hetaryl independently are substituted with one or more
R.sup.9.

64. A compound according to claim 57, wherein R.sup.7 and R.sup.8
independently are C.sub.1-C.sub.8alkyl or C.sub.3-C.sub.10cycloalkyl,
wherein the alkyl and cycloalkyl groups independently are optionally
substituted with one or more of R.sup.10.

67. A compound according to claim 57, which is:
1H-Benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide, or a salt
thereof with a pharmaceutically acceptable acid or base, or optical
isomer or mixture of optical isomers, racemic mixture, a prodrug thereof,
or tautomeric forms thereof.

68. A compound according to claim 57, selected from the group consisting
of: 1-Benzyl-1H-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide;
and (1H-Benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl-
)-methanone; or a salt thereof with a pharmaceutically acceptable acid or
base, or optical isomer or mixture of optical isomers, racemic mixture, a
prodrug thereof, or tautomeric forms thereof.

70. A compound of formula (VI): wherein X is oxygen or
(CR.sup.1R.sup.2).sub.n; R.sup.1, R.sup.2, R.sup.3, and R.sup.4
independently are hydrogen, C.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylC.sub.1-C.sub.6alkyl
optionally substituted with one or more R.sup.8 independently; or R.sup.1
and either R.sup.3 or R.sup.4 together are forming a saturated or
partially saturated ring system containing from 4 to 8 carbon atoms, the
ring system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, hydroxy, oxo, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl; or R.sup.1 and
either R.sup.3 or R.sup.4 together with the single bond are forming a
carbon-carbon double bond; R.sup.5 is C.sub.1-C.sub.8alkyl optionally
substituted with one or more of R.sup.9; R.sup.6 is
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the alkyl,
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.9; or R.sup.5 and R.sup.6 together
with the nitrogen to which they are attached, are forming a saturated or
partially saturated cyclic, bicyclic or tricyclic ring system containing
from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected
from nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.10;
R.sup.7 is hydrogen, halo, nitro, NR.sup.12R.sup.13, cyano,
trihalomethyl, C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, hetaryloxy or
hetarylC.sub.1-C.sub.6-alkyloxy optionally substituted with one or more
R.sup.11 independently; R.sup.8 and R.sup.9 independently are hydrogen,
hydroxy, oxo, halo, nitro, cyano, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6-alkyloxy, trihalomethyl, trihalomethoxy,
NR.sup.12R.sup.13, arylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 is hydrogen,
C.sub.1-C.sub.8alkyl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy; R.sup.11 is
hydrogen, halo, hydroxy, oxo, nitro, cyano, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.6alkyloxy, aryloxy or hetaryloxy; R.sup.12 and R.sup.13
independently are hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, C.sub.1-C.sub.6alkylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6alkyloxycarbonyl; or R.sup.12 and R.sup.13 are together
with the nitrogen to which they are attached, are forming a saturated or
partially saturated cyclic, bicyclic or tricyclic ring system containing
from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected
from nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or arylC.sub.1-6alkylcarboxy; n
is 1 or 2; or a salt thereof with a pharmaceutically acceptable acid or
base, or optical isomer or mixture of optical isomers, racemic mixture, a
prodrug thereof, or tautomeric forms thereof.

71. A compound according to claim 70, wherein X is
(CR.sup.1R.sup.2).sub.n.

72. A compound according to claim 70, wherein X is oxygen.

73. A compound according to claim 70, wherein R.sup.1, R.sup.2, R.sup.3,
and R.sup.4 independently are hydrogen, C.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkyl, optionally substituted with one or more
R.sup.8.

74. A compound according to claim 70, wherein R.sup.1 and either R.sup.3
or R.sup.4 together with the single bond are forming a carbon-carbon
double bond.

75. A compound according to claim 70, wherein R.sup.5 is
C.sub.1-C.sub.8alkyl optionally substituted with one or more of R.sup.9.

76. A compound according to claim 70, wherein R.sup.6 is
C.sub.3-C.sub.10cycloalkyl or C.sub.3-C.sub.10hetcycloalkyl, each of
which is optionally substituted with one or more of R.sup.9.

77. A compound according to claim 70, wherein R.sup.5 and R.sup.6 together
with the nitrogen to which they are attached, are forming a saturated or
partially saturated cyclic, bicyclic or tricyclic ring system containing
from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected
from nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.10.

78. A compound according to claim 70, wherein R.sup.7 is hydrogen, halo,
NR.sup.12R.sup.13, trihalomethyl, C.sub.1-C.sub.6alkyloxy, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, hetaryloxy optionally substituted with one
or more R.sup.11 independently.

83. A compound of formula (VII): wherein R.sup.1 is hydrogen,
C.sub.1-C.sub.8alkyl, hetaryl, arylC.sub.1-C.sub.6alkyl or
hetarylC.sub.1-C.sub.6alkyl optionally substituted with one or more
R.sup.9; R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 independently are
hydrogen, halo, nitro, cyano, trihalomethyl, carboxy,
N(R.sup.12R.sup.13), C(O)NR.sup.7R.sup.8, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
N(R.sup.12R.sup.13)C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy, arylC.sub.1-C.sub.6alkylcarboxy, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, aryloxy, aryloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyloxy,
hetaryloxyC.sub.1-C.sub.6alkyl or
hetarylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl wherein the alkyl,
aryl, arylalkyl, hetaryl and hetarylalkyl groups independently are
substituted with one or more R.sup.9; R.sup.7 is hydrogen or
C.sub.1-C.sub.8alkyl optionally substituted with one or more of R.sup.10;
R.sup.8 is C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the cycloalkyl
and hetcycloalkyl groups independently are optionally substituted with
one or more of R.sup.10; or R.sup.7 and R.sup.8 together with the
nitrogen to which they are attached, are forming a saturated or partially
saturated cyclic, bicyclic or tricyclic ring system containing from 4 to
10 carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen or oxygen, the ring system optionally being substituted with at
least one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyl-oxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.11;
R.sup.9 is hydrogen, hydroxy, oxo, halo, nitro, cyano,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy, trihalomethyl,
trihalomethoxy, NR.sup.12R.sup.13, arylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 and R.sup.11
independently are hydrogen, halo, oxo, hydroxy, C.sub.1-C.sub.6alkyl,
aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylalkyl; R.sup.12 and
R.sup.13 independently are hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, C.sub.3-C.sub.10cycloalkylcarbonyl,
C.sub.3-C.sub.10hetcycloalkylcarbonyl or
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkylcarbonyl wherein the alkyl
and aryl groups independently are optionally substituted with one or more
of R.sup.11, wherein R.sup.11 is as defined above; or R.sup.12 and
R.sup.13 together with the nitrogen to which they are attached, are
forming a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur, the
ring system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy; or a salt thereof with a
pharmaceutically acceptable acid or base, or optical isomer or mixture of
optical isomers, racemic mixture, a prodrug thereof, or tautomeric forms
thereof.

84. A compound according to claim 83, wherein R.sup.1 is hydrogen,
C.sub.1-C.sub.8alkyl, hetaryl, arylC.sub.1-C.sub.6alkyl or
hetarylC.sub.1-C.sub.6alkyl optionally substituted with one or more
R.sup.9; R.sup.2 and R.sup.5 independently are hydrogen, halo, nitro,
cyano, trihalomethyl, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6-alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, aryloxy, aryloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6-alkyloxy,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryl or
hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, aryl, arylalkyl, hetaryl
and hetarylalkyl groups independently are substituted with one or more
R.sup.9; and either R.sup.3 is C(O)NR.sup.7R.sup.8, and R.sup.4 is
hydrogen; or R.sup.3 is hydrogen, and R.sup.4 is C(O)NR.sup.7R.sup.8;
R.sup.6 is C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, N(R.sup.12R.sup.13)C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6-alkyl,
aryloxyC.sub.1-C.sub.6alkyl, arylC.sub.1-C.sub.6alkyloxy or
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl; R.sup.7 is
C.sub.1-C.sub.8alkyl optionally substituted with one or more of R.sup.10;
R.sup.8 is C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the cycloalkyl
and hetcycloalkyl groups independently are optionally substituted with
one or more of R.sup.10; or R.sup.7 and R.sup.8 together with the
nitrogen to which they are attached, are forming a saturated or partially
saturated cyclic, bicyclic or tricyclic ring system containing from 6 to
10 carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen or oxygen, the ring system optionally being substituted with at
least one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyl-oxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.11;
R.sup.9 is hydrogen, hydroxy, oxo, halo, nitro, cyano,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy, trihalomethyl,
trihalomethoxy, NR.sup.12R.sup.13, arylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 and R.sup.11
independently are hydrogen, halo, oxo, hydroxy, C.sub.1-C.sub.6alkyl,
aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylalkyl; R.sup.12 and
R.sup.13 independently are hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, C.sub.3-C.sub.10cycloalkylcarbonyl,
C.sub.3-C.sub.10hetcycloalkylcarbonyl or
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkylcarbonyl; or R.sup.12 and
R.sup.13 together with the nitrogen to which they are attached, are
forming a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur, the
ring system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy; or a salt thereof with a
pharmaceutically acceptable acid or base, or optical isomer or mixture of
optical isomers, racemic mixture, or tautomeric forms thereof.

85. A compound according to claim 83, wherein R.sup.2 is
C(O)NR.sup.7R.sup.8 and R.sup.3, R.sup.4, and R.sup.5 are hydrogen.

86. A compound according to claim 83, wherein R.sup.3 is
C(O)NR.sup.7R.sup.8 and R.sup.4 is hydrogen.

87. A compound according to claim 83, wherein R.sup.4 is
C(O)NR.sup.7R.sup.8 and R.sup.3 is hydrogen.

88. A compound according to 83, wherein R.sup.5 is C(O)NR.sup.7R.sup.8 and
R.sup.2, R.sup.3, and R.sup.4 are hydrogen.

89. A compound according to claim 83, wherein R.sup.6 is
C(O)NR.sup.7R.sup.8.

90. A compound according to claim 83, selected from the group consisting
of: (1H-Indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methan-
one; and 1H-Indole-6-carboxylic acid cyclohexyl-methyl-amide; or a salt
thereof with a pharmaceutically acceptable acid or base, or optical
isomer or mixture of optical isomers, racemic mixture, a prodrug thereof,
or tautomeric forms thereof.

92. A compound of formula (VIII): wherein X is NR.sup.4, S or O; R.sup.1
and R.sup.2 independently are hydrogen, halo, cyano, trihalomethyl,
C.sub.1-C.sub.6alkyl or C.sub.1-C.sub.6alkyloxy, wherein the alkyl groups
independently are optionally substituted with one or more of R.sup.7;
R.sup.3 is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylthio, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylalkyl, wherein the alkyl,
cycloalkyl, aryl, hetaryl and hetarylalkyl groups independently are
optionally substituted with one or more of R.sup.7; R.sup.4 is hydrogen,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryl,
hetaryl, hetarylC.sub.1-C.sub.6alkyl, arylC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl wherein the alkyl, aryl,
hetaryl, cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.7; R.sup.5 is hydrogen, and R.sup.6
is adamantyl optionally substituted with hydroxy,
C.sub.1-C.sub.6alkyloxy, aryl, arylC.sub.1-C.sub.6alkyl, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, hetaryl, hetaryloxy or
hetarylC.sub.1-C.sub.6alkyloxy wherein the alkyl, aryl and hetaryl groups
independently are optionally substituted with one or more of R.sup.7; or
R.sup.5 and R.sup.6 are together with the nitrogen to which they are
attached, forming a saturated or partially saturated cyclic, bicyclic or
tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to
2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the
ring system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylalkyl, hydroxy, oxo, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.7;
R.sup.7 are independently hydrogen, halo, hydroxy, oxo, nitro,
NR.sup.9R.sup.10, cyano, COOR.sup.8, CONR.sup.9R.sup.10,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, hetaryloxy or
hetarylC.sub.1-C.sub.6alkyloxy; R.sup.8 is hydrogen,
C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl, hetarylalkyl,
wherein the alkyl, aryl and hetarylalkyl groups independently are
optionally substituted with one or more of R.sup.7; R.sup.9 and R.sup.10
independently are hydrogen, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the alkyl,
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.7; or R.sup.9 and R.sup.10 together
with the nitrogen to which they are attached, are forming a saturated or
partially saturated bicyclic or tricyclic ring system containing from 4
to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen or oxygen, the ring system optionally being substituted with at
least one of C.sub.1-C.sub.8alkyl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6-alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.11;
R.sup.11 is hydrogen, halo, oxo, hydroxy, C.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylalkyl; provided that
hetcycloalkyl is not 7-aza[2,2,1]bicycloheptane; or a salt thereof with a
pharmaceutically acceptable acid or base, or optical isomer or mixture of
optical isomers, racemic mixture, or tautomeric forms thereof.

93. A compound according to claim 92, wherein X is NR.sup.4, S or O;
R.sup.1 and R.sup.2 independently are hydrogen, halo, cyano,
trihalomethyl, C.sub.1-C.sub.6alkyl or C.sub.1-C.sub.6alkyloxy, wherein
the alkyl groups independently are optionally substituted with one or
more of R.sup.7; R.sup.3 is hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkylthio, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or
hetarylalkyl, wherein the alkyl, cycloalkyl, aryl, hetaryl and
hetarylalkyl groups independently are optionally substituted with one or
more of R.sup.7; R.sup.4 is hydrogen, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6-alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6-alkylcarboxyC.sub.1-C.sub.6alkyl wherein the alkyl, aryl,
hetaryl, cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.7; R.sup.5 is hydrogen, and R.sup.6
is adamantyl optionally substituted with hydroxy,
C.sub.1-C.sub.6alkyloxy, aryl, arylC.sub.1-C.sub.6alkyl, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, hetaryl, hetaryloxy or
hetarylC.sub.1-C.sub.6alkyloxy wherein the alkyl, aryl and hetaryl groups
independently are optionally substituted with one or more of R.sup.7; or
R.sup.5 and R.sup.6 are together with the nitrogen to which they are
attached, forming a saturated or partially saturated cyclic, bicyclic or
tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to
2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the
ring system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylalkyl, hydroxy, oxo, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.7;
R.sup.7 are independently hydrogen, halo, hydroxy, oxo, nitro,
NR.sup.5R.sup.6, cyano, COOR.sup.8, CONR.sup.5R.sup.6,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy, aryloxy or hetaryloxy;
R.sup.8 is hydrogen, C.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetarylalkyl, wherein the alkyl, aryl and
hetarylalkyl groups independently are optionally substituted with one or
more of R.sup.7; provided that hetcycloalkyl is not
7-aza[2,2,1]bicycloheptane; or a salt thereof with a pharmaceutically
acceptable acid or base, or optical isomer or mixture of optical isomers,
racemic mixture, or tautomeric forms thereof.

94. A compound according to claim 92, wherein X is NR.sup.4 or S.

95. A compound according to claim 92, wherein R.sup.1 and R.sup.2
independently are hydrogen, halo, trihalomethyl or C.sub.1-C.sub.6alkyl,
wherein the alkyl group is optionally substituted with one or more of
R.sup.7 wherein R.sup.7.

96. A compound according to claim 92, wherein R.sup.3 is hydrogen,
C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6-alkyl, hetaryl or
hetarylalkyl, wherein the alkyl, cycloalkyl, aryl, hetaryl and
hetarylalkyl groups independently are optionally substituted with one or
more of R.sup.7 wherein R.sup.7.

97. A compound according to claim 92, wherein R.sup.4 is hydrogen,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, hetarylC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyl, wherein the alkyl, aryl, hetaryl, groups
independently are optionally substituted with one or more of R.sup.7
wherein R.sup.7.

98. A compound according to claim 92, wherein R.sup.5 and R.sup.6 are
together with the nitrogen to which they are attached, forming a
saturated or partially saturated cyclic, bicyclic or tricyclic ring
system containing from 6 to 10 carbon atoms and from 0 to 2 additional
heteroatoms selected from nitrogen, oxygen or sulphur, the ring system
optionally being substituted with at least one of C.sub.1-C.sub.6alkyl,
aryl, hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylalkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.7.

99. A compound according to claim 92, which is selected from:
(4-Methyl-2-phenyl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-
-6-yl)-methanone;
(2,4-Dimethyl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl-
)-methanone; and
(4-Methyl-2-pyrazin-2-yl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2-
.1]oct-6-yl)-methanone; or a salt thereof with a pharmaceutically
acceptable acid or base, or optical isomer or mixture of optical isomers,
racemic mixture, a prodrug thereof, or tautomeric forms thereof.

101. A compound according to any one of claims 28, 38, 39, 48, 49, 50, 51,
55, 56, 57, 58, 67, 68, 69, 70, 81, 82, 83, 90, 91, 92, 99 or 100, which
is an agent useful for the treatment, prevention and/or prophylaxis of
any conditions, disorders and diseases wherein a modulation or an
inhibition of the activity of 11.beta.HSD1 is beneficial.

102. A compound according to any one of claims 28, 38, 39, 48, 49, 50, 51,
55, 56, 57, 58, 67, 68, 69, 70, 81, 82, 83, 90, 91, 92, 99 or 100, which
is an agent useful for the treatment, prevention and/or prophylaxis of
any conditions, disorders and diseases that are influenced by
intracellular glucocorticoid levels.

103. A compound according to claim 101 or 102, which is an agent useful
for the treatment, prevention and/or prophylaxis of conditions, disorders
or diseases selected from the group consisting of the metabolic syndrome,
insulin resistance, dyslipidemia, hypertension and obesity.

104. A compound according to claim 101 or 102, which is an agent useful
for the treatment, prevention and/or prophylaxis of type 2 diabetes,
impaired glucose tolerance (IGT), impaired fasting glucose (IFG).

105. A compound according to claim 101 or 102, which is an agent useful
for the delaying or prevention of the progression from IGT into type 2
diabetes.

106. A compound according to claim 101 or 102, which is an agent useful
for delaying or prevention of the progression of the metabolic syndrome
into type 2 diabetes.

107. A compound according to claim 101 or 102, which is an agent useful
for the treatment, prevention and/or prophylaxis of adverse effects of
glucocorticoid receptor agonist treatment or therapy.

108. A pharmaceutical composition comprising, as an active ingredient, at
least one compound according to any one of claims 28, 38, 39, 48, 49, 50,
51, 55, 56, 57, 58, 67, 68, 69, 70, 81, 82, 83, 90, 91, 92, 99 or 100,
together with one or more pharmaceutically acceptable carriers or
excipients.

109. The pharmaceutical composition according to claim 108 which is for
oral, nasal, buccal, transdermal, pulmonal or parenteral administration.

110. The pharmaceutical composition according to claim 108 or 109, in unit
dosage form, comprising from 0.05 mg to 2000 mg/day, from 0.1 mg to 1000
mg or from 0.5 mg to 500 mg per day of the compound.

111. A method for the treatment, prevention and/or prophylaxis of any
conditions, disorders or diseases wherein a modulation or an inhibition
of the activity of 11.beta.HSD1 is beneficial, the method comprising
administering to a subject in need thereof an effective amount of a
compound according to any one of claims 28, 38, 39, 48, 49, 50, 51, 55,
56, 57, 58, 67, 68, 69, 70, 81, 82, 83, 90, 91, 92, 99 or 100.

112. The method according to claim 111, wherein the conditions, disorders
or diseases are selected from the group consisting of the metabolic
syndrome, insulin resistance, dyslipidemia, hypertension and obesity.

[0002] The present invention relates to use of substituted amides and
pharmaceutical compositions comprising the compounds for treating
disorders where it is desirable to modulate the activity of
11.beta.-hydroxysteroid dehydrogenase type 1 (11.beta.HSD1).

[0003] The present invention also relates to novel substituted amides, to
their use in therapy, to pharmaceutical compositions comprising the
compounds, to the use of said compounds in the manufacture of
medicaments, and to therapeutic methods comprising the administration of
said compounds. The present compounds modulate the activity of
11.beta.-hydroxysteroid dehydrogenase type 1 (11.beta.HSD1) and are
accordingly useful in the treatment of diseases in which such a
modulation is beneficial, such as the metabolic syndrome.

BACKGROUND OF THE INVENTION

[0004] The metabolic syndrome is a major global health problem. In the US,
the prevalence in the adult population is currently estimated to be
approximately 25%, and it continues to increase both in the US and
worldwide. The metabolic syndrome is characterised by a combination of
insulin resistance, dyslipidemia, obesity and hypertension leading to
increased morbidity and mortality of cardiovascular diseases. People with
the metabolic syndrome are at increased risk of developing frank type 2
diabetes, the prevalence of which is equally escalating.

[0005] In type 2 diabetes, obesity and dyslipidemia are also highly
prevalent and around 70% of people with type 2 diabetes additionally have
hypertension once again leading to increased mortality of cardiovascular
diseases.

[0006] In the clinical setting, it has long been known that
glucocorticoids are able to induce all of the cardinal features of the
metabolic syndrome and type 2 diabetes.

[0010] WO 01/90090, WO 01/90091, WO 01/90092, WO 01/90093 and WO 01/90094
discloses various thiazol-sulfonamides as inhibitors of the human
11.beta.-hydroxysteroid dehydrogenase type 1 enzyme, and further states
that said compounds may be useful in treating diabetes, obesity,
glaucoma, osteoporosis, cognitive disorders, immune disorders and
depression.

[0011] We have now found substituted amides that modulate the activity of
11.beta.HSD1 leading to altered intracellular concentrations of active
glucocorticoid. More specifically, the present compounds inhibit the
activity of 11.beta.HSD1 leading to decreased intracellular
concentrations of active glucocorticoid. Thus, the present compounds can
be used to treat disorders where a decreased level of active
intracellular glucocorticoid is desirable, such as e.g. the metabolic
syndrome, type 2 diabetes, impaired glucose tolerance (IGT), impaired
fasting glucose (IFG), dyslipidemia, obesity, hypertension, diabetic late
complications, cardiovascular diseases, arteriosclerosis,
atherosclerosis, myopathy, muscle wasting, osteoporosis,
neurodegenerative and psychiatric disorders, and adverse effects of
treatment or therapy with glucocorticoid receptor agonists.

[0012] One object of the present invention is to provide compounds,
pharmaceutical compositions and use of compounds that modulate the
activity of 11.beta.HSD1.

DEFINITIONS

[0013] In the following structural formulas and throughout the present
specification, the following terms have the indicated meaning:

[0014] The term "halo" includes fluorine, chlorine, bromine, and iodine.

[0015] The term "trihalomethyl" includes trifluoromethyl, trichloromethyl,
tribromomethyl, and triiodomethyl.

[0016] The term "trihalomethoxy" includes trifluorometoxy,
trichlorometoxy, tribromometoxy, and triiodometoxy.

[0018] The term "alkenyl" includes C.sub.2-C.sub.6 straight chain
unsaturated aliphatic hydrocarbon groups and branched C.sub.3-C.sub.6
unsaturated aliphatic hydrocarbon groups having the specified number of
carbon atoms. For example, this definition shall include but is not
limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, methylpropenyl,
methylbutenyl and the like.

[0019] The term "alkynyl" includes C.sub.2-C.sub.6 straight chain
unsaturated aliphatic hydrocarbon groups and C.sub.4-C.sub.6 branched
unsaturated aliphatic hydrocarbon groups having the specified number of
carbon atoms. For example, this definition shall include but is not
limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylbutynyl,
and the like.

[0024] The term "cycloalkylalkyl" (e.g. cyclopropylmethyl,
cyclobutylethyl, adamantylmethyl and the like) represents a cycloalkyl
group as defined above attached through an alkyl group having the
indicated number of carbon atoms or substituted alkyl group as defined
above.

[0025] The term "cycloalkenyl" (e.g. cyclobutenyl, cyclopentenyl,
cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl and
the like) represents a partially saturated, mono-, bi-, tri- or
spirocarbocyclic group having the specified number of carbon atoms.

[0026] The term "cycloalkylcarbonyl" (e.g. cyclopropylcarbonyl,
cyclohexylcarbonyl) represents an cycloalkyl group as defined above
having the indicated number of carbon atoms attached through a carbonyl
group.

[0027] The term "hetcycloalkylcarbonyl" (e.g. 1-piperidin-4-yl-carbonyl,
1-(1,2,3,4-tetrahydroisoquinolin-6-yl)carbonyl) represents an
hetcycloalkyl group as defined above having the indicated number of
carbon atoms attached through a carbonyl group.

[0028] The term "cycloalkylalkylcarbonyl" (e.g. cyclohexylmethylcarbonyl,
cycloheptylethylcarbonyl and the like) represents a cycloalkyl group as
defined above attached through an alkyl group having the indicated number
of carbon atoms or substituted alkyl group as defined above.

[0029] The term "hetcycloalkyl" (tetrahydrofuranyl, tetrahydropyranyl,
tertahydrothiopyranyl, piperidine, pyridzine and the like) represents a
saturated mono-, bi-, tri- or spirocarbocyclic group having the specified
number of carbon atoms and one or two additional heteroatoms or groups
selected from nitrogen, oxygen, sulphur, SO or SO.sub.2.

[0030] The term "hetcycloalkylalkyl" (e.g. tetrahydrofuranylmethyl,
tetrahydropyranylethyl, tertahydrothiopyranylmethyl, and the like)
represents a hetcycloalkyl group as defined above attached through an
alkyl group having the indicated number of carbon atoms or substituted
alkyl group as defined above.

[0031] The term "alkyloxy" (e.g. methoxy, ethoxy, propyloxy, allyloxy,
cyclohexyloxy) represents an alkyl group as defined above having the
indicated number of carbon atoms attached through an oxygen bridge.

[0032] The term "alkyloxyalkyl" (e.g. methyloxymethyl and the like)
represents an alkyloxy group as defined above attached through an "alkyl"
group.

[0033] The term "aryloxyhetaryl" (e.g. 2-phenoxy-pyridyl and the like)
represents an aryloxy group as defined below attached through a "hetaryl"
group.

[0034] The term "aryloxy" (e.g. phenoxy, naphthyloxy and the like)
represents an aryl group as defined below attached through an oxygen
bridge.

[0035] The term "hetaryloxy" (e.g. 2-pyridyloxy and the like) represents a
hetaryl group as defined below attached through an oxygen bridge.

[0036] The term "arylalkyloxy" (e.g. phenethyloxy, naphthylmethyloxy and
the like) represents an arylalkyl group as defined below attached through
an oxygen bridge.

[0037] The term "hetarylalkyloxy" (e.g. 2-pyridylmethyloxy and the like)
represents a hetarylalkyl group as defined below attached through an
oxygen bridge.

[0038] The term "alkyloxycarbonyl" (e.g. methylformiat, ethylformiat and
the like) represents an alkyloxy group as defined above attached through
a carbonyl group.

[0039] The term "aryloxycarbonyl" (e.g. phenylformiat, 2-thiazolylformiat
and the like) represents an aryloxy group as defined above attached
through a carbonyl group.

[0040] The term "arylalkyloxycarbonyl" (e.g. benzylformiat,
phenyletylformiat and the like) represents an "arylalkyloxy" group as
defined above attached through a carbonyl group.

[0041] The term "alkylthio" (e.g. methylthio, ethylthio and the like)
represents an alkyl group as defined above attached through a sulphur
bridge.

[0042] The term "arylthio" (e.g. benzenthiol, naphthylthiol and the like)
represents an aryl group as defined below attached through a sulphur
bridge.

[0043] The term "hetarylthio" (e.g. pyridine-2-thiol, thiazole-2-thiol and
the like) represents an hetaryl group as defined below attached through a
sulphur bridge.

[0044] The term "arylthioalkyl" (e.g. methylsulfanyl benzene,
ethylsulfanyl naphthalene and the like) represents an arylthio group as
defined below attached through an alkyl group having the indicated number
of carbon atoms.

[0045] The term "hetarylthioalkyl" (e.g. 2-methylsulfanyl-pyridine,
1-ethylsulfanyl-isoquinoline and the like) represents a hetarylthio group
as defined below attached through an alkyl group having the indicated
number of carbon atoms.

[0046] The term "hetaryloxyaryl" (e.g. 1-phenoxy-isoquinolyl,
2-phenoxypyridyl and the like) represents a hetaryloxy group as defined
above attached through an "aryl" group as defined below.

[0047] The term "hetaryloxyhetaryl" (e.g. 1-(2-pyridyloxy-isoquinoline),
2-(imidazol-2-yloxypyridine) and the like) represents a hetaryloxy group
as defined above attached through a "hetaryl" group as defined below.

[0048] The term "aryloxyalkyl" (e.g. phenoxymethyl, naphthyloxyethyl and
the like) represents an aryloxy group as defined above attached through
an "alkyl" group having the indicated number of carbon atoms.

[0049] The term "aryloxyaryl" (e.g. 1-phenoxy-naphthalene, phenyloxyphenyl
and the like) represents an aryloxy group as defined above attached
through an "aryl" group as defined below.

[0050] The term "arylalkyloxyalkyl" (e.g. ethoxymethyl-benzene,
2-methoxymethylnaphthalene and the like) represents an arylalkyloxy group
as defined above attached through an "alkyl" group having the indicated
number of carbon atoms.

[0051] The term "hetaryloxyalkyl" (e.g. 2-pyridyloxymethyl,
2-quinolyloxyethyl and the like) represents a hetaryloxy group as defined
above attached through an "alkyl" group having the indicated number of
carbon atoms.

[0052] The term "hetarylalkyloxyalkyl" (e.g. 4-methoxymethyl-pyrimidine,
2-methoxymethylquinoline and the like) represents a hetarylalkyloxy group
as defined above attached through an "alkyl" group having the indicated
number of carbon atoms.

[0053] The term "arylalkyl" (e.g. benzyl, phenylethyl, 3-phenylpropyl,
1-naphtylmethyl, 2-(1-naphtyl)ethyl and the like) represents an aryl
group as defined below attached through an alkyl having the indicated
number of carbon atoms or substituted alkyl group as defined above.

[0054] The term "hetarylalkyl" or "hetaralkyl" (e.g. (2-furyl)methyl,
(3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl,
1-methyl-1-(2-pyrimidyl)ethyl and the like) represents a hetaryl group as
defined below attached through an alkyl having the indicated number of
carbon atoms or substituted alkyl group as defined above.

[0055] The term "alkylcarbonyl" (e.g. octylcarbonyl, pentylcarbonyl,
3-hexenylcarbonyl) represents an alkyl group as defined above having the
indicated number of carbon atoms attached through a carbonyl group.

[0056] The term "arylcarbonyl" (e.g. benzoyl) represents an aryl group as
defined below attached through a carbonyl group.

[0057] The term "hetarylcarbonyl" (e.g. 2-thiophenylcarbonyl,
3-methoxy-anthrylcarbonyl, oxazolylcarbonyl and the like) represents a
hetaryl group as defined below attached through a carbonyl group.

[0058] The term "carbonylalkyl" (e.g. acetyl and the like) represents a
carbonyl group attached through alkyl group as defined above having the
indicated number of carbon atoms.

[0059] The term "alkylcarbonylalkyl" (e.g. propan-2-one,
4,4-dimethyl-pentan-2-one and the like) represents an alkylcarbonyl group
as defined above attached through an alkyl group as defined above having
the indicated number of carbon atoms.

[0060] The term "arylcarbonylalkyl" (e.g. 1-phenyl-propan-1-one,
1-(3-chloro-phenyl)-2-methylbutan-1-one and the like) represents a
arylcarbonyl group as defined above attached through an alkyl group as
defined above having the indicated number of carbon atoms.

[0061] The term "hetarylcarbonylalkyl" (e.g. 1-pyridin-2-yl-propan-1-one,
1-(1-H-imidazol-2-yl)propan-1-one and the like) represents a
hetarylcarbonyl group as defined above attached through an alkyl group as
defined above having the indicated number of carbon atoms.

[0062] The term "arylalkylcarbonyl" (e.g. phenylpropylcarbonyl,
phenylethylcarbonyl and the like) represents an arylalkyl group as
defined above having the indicated number of carbon atoms attached
through a carbonyl group.

[0063] The term "hetarylalkylcarbonyl" (e.g. imidazolylpentylcarbonyl and
the like) represents a hetarylalkyl group as defined above wherein the
alkyl group is in turn attached through a carbonyl.

[0064] The term "alkylcarbonylamino" (e.g. methylcarbonylamino,
cyclopentylcarbonylaminomethyl, methylcarbonylaminophenyl) represents an
"alkylcarbonyl" group as defined above wherein the carbonyl is in turn
attached through the nitrogen atom of an amino group. The nitrogen atom
may itself be substituted with an alkyl or aryl group.

[0065] The term "alkylcarbonylaminoalkyl" (e.g. N-propyl-acetamide,
N-butyl-propionamide and the like) represents an "alkylcarbonylamino"
group attached through an alkyl group as defined above having the
indicated number of carbon atoms.

[0066] The term "arylalkylcarbonylamino" (e.g. phenylacetamide,
3phenyl-propionamide and the like) represents an "arylalkylcarbonyl"
group as defined above attached through an amino group.

[0067] The term "arylalkylcarbonylaminoalkyl" (e.g.
N-ethyl-phenylacetamide, N-butyl-3-phenyl-propionamide and the like)
represents an "arylalkylcarbonylamino" group attached through an alkyl
group as defined above having the indicated number of carbon atoms.

[0068] The term "arylcarbonylamino" (e.g. benzamide,
naphthalene-1-carboxylic acid amide and the like) represents an
"arylcarbonyl" group as defined above attached through an amino group.

[0069] The term "arylcarbonylaminoalkyl" (e.g. N-propyl-benzamide,
N-Butyl-naphthalene-1-carboxylic acid amide and the like) represents an
"arylcarbonylamino" group attached through an alkyl group as defined
above having the indicated number of carbon atoms.

[0070] The term "alkylcarboxy" (e.g. heptylcarboxy, cyclopropylcarboxy,
3-pentenylcarboxy) represents an alkylcarbonyl group as defined above
wherein the carbonyl is in turn attached through an oxygen bridge.

[0071] The term "arylcarboxy" (e.g. benzoic acid and the like) represents
an arylcarbonyl group as defined above wherein the carbonyl is in turn
attached through an oxygen bridge.

[0073] The term "arylalkylcarboxy" (e.g. benzylcarboxy,
phenylpropylcarboxy and the like) represents an arylalkylcarbonyl group
as defined above wherein the carbonyl is in turn attached through an
oxygen bridge.

[0074] The term "arylalkylcarboxyalkyl" (e.g. benzylcarboxymethyl,
phenylpropylcarboxypropyl and the like) represents an arylalkylcarboxy
group as defined above wherein the carboxy group is in turn attached
through an alkyl group as defined above having the indicated number of
carbon atoms.

[0075] The term "hetarylcarboxy" (e.g. pyridine-2-carboxylic acid and the
like) represents a hetarylcarbonyl group as defined above wherein the
carbonyl is in turn attached through an oxygen bridge.

[0076] The term "hetarylalkylcarboxy" (e.g. (1-H-imidazol-2-yl)-acetic
acid, 3-pyrimidin-2-yl-propionic acid and the like) represents a
hetarylalkylcarbonyl group as defined above wherein the carbonyl is in
turn attached through an oxygen bridge.

[0077] The term "aryl" includes but is not limited to a carbocyclic
aromatic ring system being either monocyclic, bicyclic, or polycyclic,
such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl,
fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl and the like. Aryl
is also intended to include the partially hydrogenated derivatives of the
carbocyclic aromatic systems enumerated above. Non-limiting examples of
such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl,
1,4-dihydronaphthyl and the like.

[0078] The term "aryl1" includes phenyl, biphenyl, naphthyl, anthracenyl,
phenanthrenyl, and fluorenyl.

[0081] The term "alkylSO.sub.m" (e.g. ethylsulfonyl, ethylsulfinyl and the
like) represents an alkyl group as defined above, wherein the alkyl group
is in turn attached through a sulphur bridge wherein the sulphur is
substituted with m oxygen atoms.

[0082] The term "arylSO.sub.m" (e.g. phenylsulfinyl, naphthyl-2-sulfonyl
and the like) represents an aryl group as defined above, wherein the aryl
group is in turn attached through a sulphur bridge wherein the sulphur is
substituted with m oxygen atoms.

[0083] The term "hetarylSO.sub.m" (e.g. thiazol-2-sulfinyl,
pyridine-2-sulfonyl and the like) represents a hetaryl group as defined
above, wherein the hetaryl group is in turn attached through a sulphur
bridge wherein the sulphur is substituted with m oxygen atoms.

[0084] With respect to formula I and II, the term
"NR.sup.4R.sup.5carbonylalkyl" (e.g. N,N-dimethyl-propionamide,
N-isopropyl-N-methyl-propionamide and the like) represents
NR.sup.4R.sup.5 substituted by a carbonylalkyl group as defined above.

[0085] With respect to formula I and II, the term "alkylR.sup.6alkyl"
(e.g. 2-ethoxymethyl, N-ethyl-N-methy amine, methyl-propyl-amide,
ethanesulfonic acid methylamide and the like) represents an alkyl group
as defined above, substituted by R.sup.6, which is substituted by an
alkyl group as defined above.

[0086] With respect to formula I and II, the term "arylR.sup.6alkyl" (e.g.
ethoxy-benzene, N-ethyl-N-methyl-phenyl-amine, N-ethyl-benzamide,
N-isobutyl-benzenesulfonamide and the like) represents an aryl group as
defined above, substituted by R.sup.6, which is substituted by an alkyl
group as defined above.

[0087] With respect to formula I and II, the term "arylalkylR.sup.6alkyl"
(e.g. benzyloxymethyl, N-ethyl-N-methyl-benzyl-amine, N-ethyl-benzylamide
and the like) represents an arylalkyl group as defined above, substituted
by R.sup.6, which is substituted by an alkyl group as defined above.

[0088] With respect to formula I and II, the term "hetarylR.sup.6alkyl"
(e.g. 2-ethoxy-1H-imidazol, ethyl-quinolin-2-yl-amine,
thiazole-2-carboxylic acid, methyl-propyl-amide, pyridine-3-sulfonic acid
isobutyl-amide and the like) represents a hetaryl group as defined above,
substituted by R.sup.6, which is substituted by an alkyl group as defined
above.

[0089] With respect to formula I and II, the term "arylcarbonylNR.sup.15"
(e.g. N-benzyl-N-methyl-benzamide and the like) represents an
arylcarbonyl group as defined above, substituted by NR.sup.15.

[0090] With respect to formula I and II, the term "arylSO.sub.mNR.sup.8"
(e.g. N-methyl-benzenesulfonamide and the like) represents an aryl group
as defined above, wherein the aryl group is in turn attached through a
SO.sub.mNR.sup.8 group wherein the sulphur is substituted with m oxygen
atoms and the nitrogen atom substituted by R.sup.8.

[0091] With respect to formula III, the term "alkylNR.sup.5alkyl" (e.g.
N-ethyl-N-isobutyl-amine, N,N-dimethylamine and the like wherein the
amino group (N) is substituted with R.sup.5 as defined below) represents
an alkylNR.sup.5 group as defined above attached through an "alkyl"
group.

[0092] With respect to formula III, the term "arylalkylNR.sup.5alkyl"
(e.g. N-benzyl-N-methyl-amine, N-phenethyl-N-ethyl-amine and the like
wherein the amino group (N) is substituted with R.sup.5 as defined below)
represents an arylalkylNR.sup.5 group as defined above attached through
an "alkyl" group.

[0093] Certain of the above defined terms may occur more than once in the
structural formulae, and upon such occurrence each term shall be defined
independently of the other.

[0094] The term "optionally substituted" as used herein means that the
groups in question are either unsubstituted or substituted with one or
more of the substituents specified. When the groups in question are
substituted with more than one substituent, the substituents may be the
same or different.

[0095] The term "treatment" is defined as the management and care of a
patient for the purpose of combating or alleviating the disease,
condition or disorder, and the term includes the administration of the
active compound to prevent the onset of the symptoms or complications, or
alleviating the symptoms or complications, or eliminating the disease,
condition, or disorder.

[0096] The term "pharmaceutically acceptable" is defined as being suitable
for administration to humans without adverse events.

[0097] The term "prodrug" is defined as a chemically modified form of the
active drug, said prodrug being administered to the patient and
subsequently being converted to the active drug. Techniques for
development of prodrugs are well known in the art.

DETAILED DESCRIPTION OF THE INVENTION

[0098] In one aspect, the present invention provides the use of a
substituted amide, a prodrug thereof, or a salt thereof with a
pharmaceutically acceptable acid or base, or any optical isomer or
mixture of optical isomers, including a racemic mixture, or any
tautomeric forms for

a) modulation of the activity of 11.beta.HSD1; or

b) inhibition of 11.beta.HSD1,

in a patient in need thereof.

[0099] In another aspect, the present invention provides the use of a
substituted amide, a prodrug thereof, or a salt thereof with a
pharmaceutically acceptable acid or base, or any optical isomer or
mixture of optical isomers, including a racemic mixture, or any
tautomeric forms for the preparation of a pharmaceutical composition for
the treatment, prevention and/or prophylaxis of any disorder and disease
where it is desirable to

[0101] In another embodiment, the invention provides the present use of a
substituted amide, or a prodrug thereof of the above general formula (I)
wherein

[0102] R.sup.1 is C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl, wherein the
cycloalkyl, hetcycloalkyl, alkyl, arylalkyl and hetarylalkyl groups
independently are optionally substituted with one or more of R.sup.4;

R.sup.2 is hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl wherein the alkyl, aryl
and cycloalkyl groups independently are optionally substituted with one
or more of R.sup.5; or

[0103] R.sup.1 and R.sup.2 are together with the nitrogen to which they
are attached, are forming a saturated or partially saturated cyclic,
bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms
and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or
sulphur, the ring system optionally being substituted with at least one
of C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or arylC.sub.1-6alkylcarboxy
wherein the alkyl and aryl groups independently are optionally
substituted with one or more of R.sup.14;

R.sup.8 and R.sup.9 independently are hydrogen, C.sub.1-C.sub.8alkyl,
aryl, hetaryl, arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl
wherein the alkyl, aryl and hetaryl groups independently are optionally
substituted with one or more of R.sup.11; or

[0107] R.sup.8 and R.sup.9 together with the nitrogen to which they are
attached, are forming a saturated or partially saturated cyclic, bicyclic
or tricyclic ring system containing from 4 to 10 carbon atoms and from 0
to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the
ring system optionally being substituted with at least one
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy, hetarylcarboxy,
arylC.sub.1-C.sub.6alkyl-carboxy or hetarylC.sub.1-C.sub.6alkylcarboxy;

a salt thereof with a pharmaceutically acceptable acid or base, or any
optical isomer or mixture of optical isomers, including a racemic
mixture, or any tautomeric forms.

[0109] In another embodiment, the invention provides the present use of a
substituted amide, or a prodrug thereof of the general formula (I)
wherein R.sup.1 is C.sub.3-C.sub.10cycloalkyl or
C.sub.3-C.sub.10hetcycloalkyl wherein the cycloalkyl and hetcycloalkyl
groups independently are optionally substituted with one or more of
R.sup.4 as defined above.

[0110] In another embodiment, the invention provides the present use of a
substituted amide, or a prodrug thereof of the general formula (I)
wherein R.sup.1 is C.sub.3-C.sub.10cycloalkyl optionally substituted with
one or more of R.sup.4 as defined above.

[0111] In another embodiment, the invention provides the present use of a
substituted amide, or a prodrug thereof of the general formula (I)
wherein R.sup.2 is hydrogen or C.sub.1-C.sub.8alkyl, wherein the alkyl
group is optionally substituted with one or more of R.sup.5 as defined
above.

[0112] In another embodiment, the invention provides the present use of a
substituted amide, or a prodrug thereof of the general formula (I)
wherein R.sup.2 is C.sub.1-C.sub.8alkyl optionally substituted with one
or more of R.sup.5 as defined above.

[0113] In another embodiment, the invention provides the present use of a
substituted amide, or a prodrug thereof of the general formula (I)
wherein R.sup.3 is C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, aryl-R.sup.6--C.sub.1-C.sub.6alkyl,
hetaryl-R.sup.6--C.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl wherein the alkyl,
cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are
optionally substituted with one or more of R.sup.7.

[0114] In another embodiment, the invention provides the present use of a
substituted amide, or a prodrug thereof of the general formula (I)
wherein R.sup.3 is aryl or hetaryl, wherein the aryl and hetaryl groups
are optionally substituted with one or more of R.sup.7 as defined above.

[0115] In another embodiment, the invention provides the present use of a
substituted amide, or a prodrug thereof of the general formula (I)
wherein R.sup.3 is phenyl optionally substituted with one or more of
R.sup.7 as defined above.

[0116] In another embodiment, the invention provides the present use of a
substituted amide, or a prodrug thereof of the general formula (I)
wherein R.sup.3 is phenyl optionally substituted independently in
position 2(ortho) or 4(para) with one or more of R.sup.7 as defined
above.

[0117] In another embodiment, the invention provides the present use of a
substituted amide, or a prodrug thereof of the general formula (I)
wherein R.sup.4 and R.sup.5 independently are hydrogen, hydroxy, oxo,
halo, C.sub.1-C.sub.8alkyl, wherein the alkyl group is optionally
substituted with one or more of R.sup.15.

[0118] In another embodiment, the invention provides the present use of a
substituted amide, or a prodrug thereof of the general formula (I)
wherein R.sup.6 is oxygen.

[0120] In another embodiment, the invention provides the present use of a
substituted amide, or a prodrug thereof of the general formula (I)
wherein R.sup.8 and R.sup.9 together with the nitrogen to which they are
attached, are forming a saturated or partially saturated cyclic, bicyclic
or tricyclic ring system containing from 4 to 10 carbon atoms and from 0
to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the
ring system optionally being substituted with at least one halo, cyano,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy, hetarylcarboxy,
arylC.sub.1-C.sub.6alkylcarboxy or hetarylC.sub.1-C.sub.6alkylcarboxy.

[0121] In another embodiment, the invention provides the present use of a
substituted amide, or a prodrug thereof of the general formula (I)
wherein R.sup.15 is CONR.sup.8R.sup.9.

[0860] In another embodiment, the present invention is concerned the
substituted amides or prodrugs thereof of the general formula (II)
wherein R.sup.1 is C.sub.3-C.sub.10cycloalkyl or
C.sub.3-C.sub.10hetcycloalkyl, wherein the cycloalkyl and hetcycloalkyl
groups independently are optionally substituted with one or more of
R.sup.4; R.sup.2 is hydrogen, C.sub.1-C.sub.8alkyl,
arylC.sub.1-C.sub.6alkyl, wherein the alkyl and aryl groups independently
are optionally substituted with one or more of R.sup.5; or R.sup.1 and
R.sup.2 together with the nitrogen to which they are attached, are
forming a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur, the
ring system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.14;
R.sup.3 is C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
aryl or hetaryl, wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and
hetaryl groups independently are optionally substituted with one or more
of R.sup.7; R.sup.4 and R.sup.5 independently are hydrogen, hydroxy,
oxo, cyano, halo, methylendioxo, NR.sup.8R.sup.9, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.6alkyloxy, trihalomethyl, trihalomethyloxy,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkenyl, aryl, hetaryl, hetarylSO.sub.n,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylSO.sub.n,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy, hetarylcarboxy,
arylC.sub.1-C.sub.6alkylcarboxy or hetarylC.sub.1-C.sub.6alkylcarboxy
wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups
independently are optionally substituted with one or more of R.sup.15;
R.sup.6 is oxygen, sulphur, SO.sub.n or NR.sup.16; R.sup.7 is hydrogen,
halo, hydroxy, cyano, nitro, COOR.sup.17, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl, methylendioxo,
trihalomethyl, trihalomethyloxy, aryl, arylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
aryloxy, arylC.sub.1-C.sub.6alkyloxy, aryloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, hetaryloxy, hetarylC.sub.1-C.sub.6alkyloxy,
hetaryloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl, NR.sup.8R.sup.9,
SO.sub.mNR.sup.8R.sup.9, NR.sup.4R.sup.5carbonylC.sub.1-C.sub.6alkyl,
arylthio, hetarylthio, R.sup.18-carbonylNR.sup.8, arylSO.sub.n,
hetarylSO.sub.n, R.sup.19SO.sub.mNR.sup.8, arylthioC.sub.1-C.sub.6alkyl,
hetarylthioC.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkylR.sup.6C.sub.1-C.sub.6alkyl; wherein the aryl and
hetaryl groups independently are optionally substituted with one or more
R.sup.10; R.sup.8 and R.sup.9 independently are hydrogen,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, C.sub.1-C.sub.6alkylSO.sub.m,
arylSO.sub.m, arylC.sub.1-C.sub.6alkylSO.sub.m, arylC.sub.1-C.sub.6alkyl
or hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, aryl and hetaryl groups
independently are optionally substituted with one or more of R.sup.11; or
R.sup.8 and R.sup.9 together with the nitrogen to which they are
attached, are forming a saturated or partially saturated cyclic, bicyclic
or tricyclic ring system containing from 4 to 10 carbon atoms and from 0
to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the
ring system optionally being substituted with at least one halo, cyano,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy, hetarylcarboxy,
arylC.sub.1-C.sub.6alkylcarboxy or hetarylC.sub.1-C.sub.6alkylcarboxy;
R.sup.10 and R.sup.11 independently are hydrogen, hydroxy, oxo, halo,
cyano, nitro, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyl-oxy,
NR.sup.12R.sup.13, methylendioxo, trihalomethyl or trihalomethyloxy;
R.sup.12 and R.sup.13 independently are hydrogen, C.sub.1-C.sub.8alkyl or
arylC.sub.1-C.sub.6alkyl; R.sup.14 is hydrogen, halo, hydroxy, oxo,
nitro, cyano, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy or aryloxy;
R.sup.15 is hydrogen, halo, hydroxy, oxo, nitro, cyano, CONR.sup.8R.sup.9
or COOR.sup.17; R.sup.16 is hydrogen, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl, hetarylC.sub.1-C.sub.6alkyl,
alkylcarbonyl, arylcarbonyl, arylC.sub.1-C.sub.6alkylcarbonyl,
aryloxyC.sub.1-C.sub.6alkyl, hetaryloxyC.sub.1-C.sub.6alkyl,
arylthioC.sub.1-C.sub.6alkyl or hetarylthioC.sub.1-C.sub.6alkyl; wherein
the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups
independently are optionally substituted with one or more of R.sup.10;
R.sup.17 is hydrogen, C.sub.1-C.sub.8alkyl, aryl or
arylC.sub.1-C.sub.6alkyl; R.sup.18 is C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, C.sub.1-C.sub.6alkyloxy, aryloxy,
arylC.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryloxy,
hetarylC.sub.1-C.sub.6alkyloxy or R.sup.8R.sup.9NC.sub.1-C.sub.6alkyl
wherein the alkyl, alkenyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl
groups are optionally substituted with R.sup.15; R.sup.19 is
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl; m is 1 or 2; n is 0, 1 or 2; or a salt
thereof with a pharmaceutically acceptable acid or base, or any optical
isomer or mixture of optical isomers, including a racemic mixture, or any
tautomeric forms.

[0861] In another embodiment of the present invention, in formula (II)
R.sup.1 is C.sub.3-C.sub.10cycloalkyl or C.sub.3-C.sub.10hetcycloalkyl,
wherein the cycloalkyl and hetcycloalkyl groups independently are
optionally substituted with one or more of R.sup.4 as defined above.

[0862] In another embodiment of the present invention, in formula (II)
R.sup.2 is hydrogen or C.sub.1-C.sub.8alkyl, wherein the alkyl group is
optionally substituted with one or more of R.sup.5 as defined above.

[0863] In another embodiment of the present invention, in formula (II)
R.sup.1 and R.sup.2 together with the nitrogen to which they are
attached, are forming a saturated or partially saturated cyclic, bicyclic
or tricyclic ring system containing from 4 to 10 carbon atoms and from 0
to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur,
the ring system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.14; as
defined above.

[0864] In another embodiment of the present invention, in formula (II)
R.sup.1 and R.sup.2 together with the nitrogen to which they are attached
are 6-aza-bicyclo[3.2.1]octane.

[0865] In another embodiment of the present invention, in formula (II)
R.sup.3 is aryl or hetaryl, wherein the aryl and hetaryl groups
independently are optionally substituted with one or more of R.sup.7 as
defined above.

In another embodiment of the present invention, in formula (II) R.sup.3
is C.sub.3-C.sub.10cycloalkyl or C.sub.3-C.sub.10hetcycloalkyl,
optionally substituted with one or more of R.sup.7 as defined above.

[0866] In another embodiment of the present invention, in formula (II)
R.sup.4 and R.sup.5 independently are hydrogen, hydroxy, oxo, halo,
C.sub.1-C.sub.8alkyl, wherein the alkyl group is optionally substituted
with one or more of R.sup.15 as defined above.

[0869] In another embodiment of the present invention, in formula (II)
R.sup.7 is R.sup.18-carbonylNR.sup.8 or R.sup.19SO.sub.mNR.sup.8; wherein
m, R.sup.8, R.sup.18 and R.sup.19 are defined as above.

[0870] In another embodiment of the present invention, in formula (II)
R.sup.8 is C.sub.1-C.sub.6alkyl.

[0871] In another embodiment of the present invention, in formula (II)
R.sup.8 and R.sup.9 together with the nitrogen to which they are
attached, are forming a saturated or partially saturated cyclic, bicyclic
or tricyclic ring system containing from 4 to 10 carbon atoms and from 0
to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the
ring system optionally being substituted with at least one halo, cyano,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy, hetarylcarboxy,
arylC.sub.1-C.sub.6alkylcarboxy or hetarylC.sub.1-C.sub.6alkylcarboxy.

[0872] In another embodiment of the present invention, in formula (II)
R.sup.15 is CONR.sup.8R.sup.9.

[0873] In another embodiment of the present invention, in formula (II)
R.sup.18 is C.sub.1-C.sub.6alkyl, optionally substituted with R.sup.15 as
defined above.

[0874] In another embodiment of the present invention, in formula (II)
R.sup.18 is aryl or hetaryl.

[0875] In another embodiment of the present invention, in formula (II)
R.sup.18 is arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl or
hetarylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl.

[0876] In another embodiment of the present invention, in formula (II)
R.sup.18 is R.sup.8R.sup.9NC.sub.1-C.sub.6alkyl; wherein R.sup.8 and
R.sup.9 are defined as above.

[0877] In another embodiment of the present invention, in formula (II)
R.sup.19 is aryl or hetaryl

[0878] In another embodiment of the present invention, in formula (II) the
aryl group is phenyl or pyridyl.

[0879] In another embodiment of the present invention, in formula (II) the
hetaryl group is thienyl, imidazolyl, oxazolyl, thiazolyl, or indolyl.

[0880] In another embodiment of the present invention, the compounds or
prodrugs thereof of the general formula (II) are selected from the group
consisting of the compounds of examples 4 through 8 as described under
EXAMPLES, COMPOUNDS OF GENERAL FORMULAS (I) AND (II).

[0881] In another embodiment, the present invention concerns the
substituted amides or prodrugs thereof of the general formula (III)
wherein R.sup.1 is aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or
hetarylC.sub.1-C.sub.6alkyl optionally substituted with one or more of
R.sup.6 independently; R.sup.2 is halo, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, trihalomethyl, aryl,
arylC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6-alkylNR.sup.5C.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkylNR.sup.5C.sub.1-C.sub.6alkyl, hetaryl or
hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, alkenyl, alkynyl,
cycloalkyl and aryl groups independently are optionally substituted with
one or more R.sup.7; R.sup.3 is C.sub.1-C.sub.6alkyl optionally
substituted with one or more of R.sup.8; R.sup.4 is
C.sub.6-C.sub.10cycloalkyl, C.sub.6-C.sub.10hetcycloalkyl,
C.sub.6-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl or
C.sub.6-C.sub.10hetcycloalkylC.sub.1-C.sub.6alkyl wherein the alkyl,
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.8; or R.sup.3 and R.sup.4 together
with the nitrogen to which they are attached, are forming a saturated or
partially saturated bicyclic/bridge ring system containing from 7 to 12
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being substituted
with at least one of C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy, wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.9;
R.sup.5 is C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10-cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10hetcycloalkylC.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl wherein the
alkyl, alkenyl, alkynyl, aryl, hetaryl, cycloalkyl and hetcycloalkyl
groups independently are optionally substituted with one or more of
R.sup.9; R.sup.6 and R.sup.7 independently are hydrogen, hydroxy, oxo,
halo, nitro, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6-alkyloxy,
trihalomethyl, trihalomethoxy, NR.sup.10R.sup.11,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6-alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkyloxycarbonyl,
aryloxycarbonyl, arylC.sub.1-C.sub.6alkyloxycarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy; R.sup.8 and R.sup.9 independently are
hydrogen, C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6-alkyl, hydroxy, oxo, cyano, NR.sup.10R.sup.11,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy,
hetaryloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 and R.sup.11 independently are
hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl; or R.sup.10 and
R.sup.11 together with the nitrogen to which they are attached, are
forming a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur, the
ring system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or arylC.sub.1-6-alkylcarboxy;
or a salt thereof with a pharmaceutically acceptable acid or base, or
any optical isomer or mixture of optical isomers, including a racemic
mixture, or any tautomeric forms.

[0882] In another embodiment, the present invention is concerned with
compounds or prodrugs thereof of the general formula (III) wherein:

R.sup.1 is aryl or hetaryl optionally substituted with one or more
R.sup.6 independently;

R.sup.3 is C.sub.1-C.sub.6alkyl optionally substituted with one or more
of R.sup.8;

R.sup.4 is C.sub.6-C.sub.10cycloalkyl, C.sub.6-C.sub.10hetcycloalkyl,
C.sub.6-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl or
C.sub.6-C.sub.10hetcycloalkylC.sub.1-C.sub.6alkyl wherein the alkyl,
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.8;

[0887] R.sup.10 and R.sup.11 together with the nitrogen to which they are
attached, are forming a saturated or partially saturated cyclic, bicyclic
or tricyclic ring system containing from 4 to 10 carbon atoms and from 0
to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur,
the ring system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy, hetaryl
C.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or arylC.sub.1-6-alkylcarboxy;
or

a salt thereof with a pharmaceutically acceptable acid or base, or any
optical isomer or mixture of optical isomers, including a racemic
mixture, a prodrug thereof, or any tautomeric forms.

[0888] In another embodiment of the present invention, in formula (III)
R.sup.1 is aryl, arylC.sub.1-C.sub.6alkyl or hetaryl optionally
substituted with one or more of R.sup.6.

[0889] In another embodiment of the present invention, in formula (III)
R.sup.1 is aryl optionally substituted with one or more of R.sup.6.

[0890] In another embodiment of the present invention, in formula (III)
R.sup.1 is arylC.sub.1-C.sub.6alkyl optionally substituted with one or
more of R.sup.6.

[0891] In another embodiment of the present invention, in formula (III)
R.sup.1 is hetaryl optionally substituted with one or more of R.sup.6.

[0892] In another embodiment of the present invention, in formula (III)
R.sup.2 is C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, trihalomethyl,
arylC.sub.1-C.sub.6alkyl, or hetarylC.sub.1-C.sub.6alkyl wherein the
alkyl, cycloalkyl and aryl groups independently are optionally
substituted with one or more R.sup.7.

[0893] In another embodiment of the present invention, in formula (III)
R.sup.2 is C.sub.1-C.sub.6alkyl optionally substituted with one or more
R.sup.7.

[0894] In another embodiment of the present invention, in formula (III)
R.sup.2 is trihalomethyl.

[0895] In another embodiment of the present invention, in formula (III)
R.sup.3 is C.sub.1-C.sub.6alkyl optionally substituted with one or more
of R.sup.8.

[0896] In another embodiment of the present invention, in formula (III)
R.sup.4 is C.sub.6-C.sub.10cycloalkyl, or C.sub.6-C.sub.10hetcycloalkyl,
wherein the cycloalkyl and hetcycloalkyl groups independently are
optionally substituted with one or more of R.sup.8.

[0897] In another embodiment of the present invention, in formula (III)
R.sup.4 is C.sub.6-C.sub.10cycloalkyl optionally substituted with one or
more of R.sup.8.

[0898] In another embodiment of the present invention, in formula (III)
R.sup.4 is C.sub.6C.sub.6-C.sub.10hetcycloalkyl optionally substituted
with one or more of R.sup.8.

[0899] In another embodiment of the invention, in formula (III) R.sup.3
and R.sup.4 together with the nitrogen to which they are attached, are
forming a saturated or partially saturated bicyclic/bridge ring system
containing from 7 to 12 carbon atoms and from 0 to 2 additional
heteroatoms selected from nitrogen, oxygen or sulphur, the ring system
optionally being substituted with at least one of C.sub.1-C.sub.6alkyl,
aryl, hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
hydroxy, oxo, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy, wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.9.

[0900] In another embodiment of the present invention, in formula (III)
the saturated or partially saturated bicyclic/bridge ring system is
6-aza-bicyclo[3.2.1]octane.

[0902] In another embodiment of the present invention, in formula (III)
R.sup.8 and R.sup.9 independently are hydrogen, C.sub.1-C.sub.6alkyl,
hydroxy, oxo, C.sub.1-C.sub.6alkyloxy or arylC.sub.1-C.sub.6alkyloxy.

[0903] In another embodiment of the present invention, in formula (III)
R.sup.10 and R.sup.11 independently are hydrogen or C.sub.1-C.sub.8alkyl.

[0904] In another embodiment of the present invention the compound of the
general formula (III) or a prodrug thereof is
1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide or a salt thereof with a pharmaceutically
acceptable acid or base, or any optical isomer or mixture of optical
isomers, including a racemic mixture, or any tautomeric forms.

[0905] In another embodiment of the present invention the compounds of the
general formula (III) or a prodrug thereof is selected from the group
consisting of: [0906]
1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide; [0907]
[1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-(1,3,3-trimethyl-6-aza-bi-
cyclo[3.2.1]oct-6-yl)-methanone; [0908] 1
[1-(4-Chloro-phenyl)-5-propyl-1H-pyrazol-4-yl]-(1,3,3-trimethyl-6-aza-bic-
yclo[3.2.1]oct-6-yl)-methanone; [0909]
[1-(3,5-Dichloro-phenyl)-5-propyl-1H-pyrazol-4-yl]-(1,3,3-trimethyl-6-aza-
-bicyclo[3.2.1]oct-6-yl)-methanone; or a salt thereof with a
pharmaceutically acceptable acid or base, or any optical isomer or
mixture of optical isomers, including a racemic mixture, or any
tautomeric forms.

[0910] In yet another embodiment of the present invention the compounds of
the general formula (III) or a prodrug thereof is selected from the group
consisting of: [0911] 1-(Phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide; [0912]
1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide; [0913]
1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide; [0914]
1-(4-Chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide; [0915]
1-(2-Methyl-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide; [0916]
1-(4-Amino-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide; [0917]
1-(2-Pyridyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide; [0918]
1-(2-Pyridyl)-5-propyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically
acceptable acid or base, or any optical isomer or mixture of optical
isomers, including a racemic mixture, or any tautomeric forms.

[0919] In another embodiment, the present invention is concerned with
compounds or prodrugs thereof of the general formula (IV) wherein
R.sup.1 is hydrogen, trihalomethyl, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylthio, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetaralkyl, wherein the alkyl, aryl
and hetaryl groups independently are optionally substituted with one or
more of R.sup.8; R.sup.2, R.sup.3, R.sup.4 and R.sup.5 independently are
hydrogen, halo, nitro, cyano, hydroxy, NR.sup.9R.sup.10, trihalomethyl,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylthio,
aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or hetaralkyl, wherein the alkyl,
aryl and hetaryl groups independently are optionally substituted with one
or more of R.sup.8; or R.sup.2 together with R.sup.3 are forming a
saturated or partially saturated cyclic ring system containing from 3 to
6 carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being substituted
with at least one of C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy; or R.sup.3 together with R.sup.4 are
forming a saturated or partially saturated cyclic ring system containing
from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected
from nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy; or R.sup.4 together with R.sup.5 are
forming a saturated or partially saturated cyclic ring system containing
from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected
from nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy; R.sup.6 is aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl, wherein the alkyl, aryl
and cycloalkyl groups independently are optionally substituted with one
or more of R.sup.11; R.sup.7 is C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl, wherein the alkyl, aryl
and cycloalkyl groups independently are optionally substituted with one
or more of R.sup.11; or R.sup.6 and R.sup.7, together with the nitrogen
to which they are attached, are forming a saturated or partially
saturated cyclic, bicyclic or tricyclic ring system containing from 6 to
10 carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being substituted
with at least one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6-alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.8;
R.sup.9 and R.sup.10 independently are hydrogen, C.sub.1-C.sub.8alkyl,
aryl, hetaryl, arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl, wherein the alkyl, aryl
and cycloalkyl groups independently are optionally substituted with one
or more of R.sup.11; or R.sup.9 and R.sup.10, together with the nitrogen
to which they are attached, are forming a saturated or partially
saturated cyclic, bicyclic or tricyclic ring system containing from 4 to
10 carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being substituted
with at least one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6-alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.8;
R.sup.8 and R.sup.11 independently are hydrogen, halo, hydroxy, oxo,
nitro, cyano, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6-alkyloxy or aryloxy;
or a salt thereof with a pharmaceutically acceptable acid or base, or
any optical isomer or mixture of optical isomers, including a racemic
mixture, or any tautomeric forms.

[0920] In one embodiment of the present invention, in formula (IV) R.sup.1
is hydrogen or C.sub.1-C.sub.6alkyl, wherein the alkyl group is
optionally substituted with one or more of R.sup.8.

[0921] In another embodiment of the present invention, in formula (IV)
R.sup.1 is hydrogen.

[0922] In another embodiment of the present invention, in formula (IV)
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are hydrogen.

[0923] In another embodiment of the present invention, in formula (IV)
R.sup.3 together with R.sup.4 are forming a saturated or partially
saturated cyclic ring system containing from 3 to 6 carbon atoms and from
0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, C.sub.1-C.sub.6alkyloxy,
aryloxy, arylC.sub.1-C.sub.6alkyloxy or hetarylC.sub.1-C.sub.6alkyloxy.

[0924] In another embodiment of the present invention, in formula (IV)
R.sup.4 together with R.sup.5 are forming a saturated or partially
saturated cyclic ring system containing from 3 to 6 carbon atoms and from
0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, C.sub.1-C.sub.6alkyloxy,
aryloxy, arylC.sub.1-C.sub.6alkyloxy or hetarylC.sub.1-C.sub.6alkyloxy.

[0925] In another embodiment of the present invention, in formula (IV)
R.sup.6 and R.sup.7, together with the nitrogen to which they are
attached, are forming a saturated or partially saturated cyclic, bicyclic
or tricyclic ring system containing from 6 to 10 carbon atoms and from 0
to 2 additional heteroatoms selected from nitrogen or oxygen, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.8;

[0926] In another embodiment of the present invention, in formula (IV)
R.sup.6 and R.sup.7; together with the nitrogen to which they are
attached, are forming a saturated or partially saturated bicyclic or
tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to
2 additional heteroatoms selected from nitrogen or oxygen, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6-alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.8.

[0927] In another embodiment of the present invention, in formula (IV)
R.sup.9 and R.sup.10, together with the nitrogen to which they are
attached, are forming a saturated or partially saturated cyclic, bicyclic
or tricyclic ring system containing from 4 to 10 carbon atoms and from 0
to 2 additional heteroatoms selected from nitrogen or oxygen, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.8.

[0928] In another embodiment of the present invention a compound of the
general formula (IV) or a prodrug thereof is
pyrazolo[1,5-a]pyridin-3-yl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl-
)-methanone; or a salt thereof with a pharmaceutically acceptable acid or
base, or any optical isomer or mixture of optical isomers, including a
racemic mixture, or any tautomeric forms.

[0929] In another embodiment of the present invention the compounds of the
general formula (IV) or a prodrug thereof are: [0930]
(2-Methyl-pyrazolo[1,5-a]pyridin-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2-
.1]oct-6-yl)-methanone; [0931] Pyrazolo[1,5-a]pyridine-3-carboxylic acid
cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically
acceptable acid or base, or any optical isomer or mixture of optical
isomers, including a racemic mixture, or any tautomeric forms.

[0932] In another embodiment, the present invention is concerned with
compounds or prodrugs thereof of the general formula (V) Accordingly,
the present invention is concerned with compounds or prodrugs thereof of
the general formula (V): wherein R.sup.1 is hydrogen,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6SO.sub.2, arylSO.sub.2, hetarylSO.sub.2,
arylC.sub.1-C.sub.6alkylSO.sub.2 or hetarylC.sub.1-C.sub.6alkylSO.sub.2
all of which is optionally substituted with one or more R.sup.8; R.sup.2
and R.sup.5 independently are hydrogen, halo, nitro, cyano,
trihalomethyl, C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl,
hetaryl or hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, aryl,
arylalkyl, hetaryl and hetarylalkyl groups independently are substituted
with one or more R.sup.9; and either R.sup.3 is hydrogen; and R.sup.4 is
C(O)NR.sup.7R.sup.8; or R.sup.3 is C(O)NR.sup.7R.sup.8; and R.sup.4 is
hydrogen; and R.sup.6 is hydrogen, halo, cyano, trihalomethyl,
NR.sup.12R.sup.13, C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl,
hetaryl or hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, aryl,
arylalkyl, hetaryl and hetarylalkyl groups independently are substituted
with one or more R.sup.9; and R.sup.7 and R.sup.8 independently are
C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the alkyl,
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.10; or R.sup.7 and R.sup.8
together with the nitrogen to which they are attached, are forming a
saturated or partially saturated bicyclic or tricyclic ring system
containing from 6 to 10 carbon atoms and from 0 to 2 additional
heteroatoms selected from nitrogen or oxygen, the ring system optionally
being substituted with at least one of C.sub.1-C.sub.8alkyl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.11;
R.sup.9 is hydrogen, hydroxy, oxo, halo, nitro, cyano,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy, trihalomethyl,
trihalomethoxy, NR.sup.12R.sup.13, C(O)NR.sup.12R.sup.13,
arylC.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 and R.sup.11
independently are hydrogen, halo, oxo, hydroxy, C.sub.1-C.sub.6alkyl,
aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylalkyl; R.sup.12 and
R.sup.13 independently are hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.8alkylcarbonyl, hetarylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl; or R.sup.12 and
R.sup.13 together with the nitrogen to which they are attached, are
forming a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur, the
ring system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkyl-carbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy; or a salt thereof with a
pharmaceutically acceptable acid or base, or any optical isomer or
mixture of optical isomers, including a racemic mixture, a prodrug
thereof, or any tautomeric forms.

[0933] In another embodiment, the present invention is concerned with
compounds or prodrugs thereof of the general formula (Va) wherein
R.sup.1 is hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl optionally
substituted with one or more R.sup.8; R.sup.2 and R.sup.5 independently
are hydrogen, halo, nitro, cyano, trihalomethyl, C.sub.1-C.sub.6alkyl,
aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylC.sub.1-C.sub.6alkyl
wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups
independently are substituted with one or more R.sup.8; and either
R.sup.3 is hydrogen; and R.sup.4 is C(O)NR.sup.6R.sup.7; or R.sup.3 is
C(O)NR.sup.6R.sup.7; and R.sup.4 is hydrogen; R.sup.6 and R.sup.7
independently are C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the alkyl,
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.9; or R.sup.6 and R.sup.7 together
with the nitrogen to which they are attached, are forming a saturated or
partially saturated bicyclic or tricyclic ring system containing from 6
to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen or oxygen, the ring system optionally being substituted with at
least one of C.sub.1-C.sub.8alkyl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.10;
R.sup.8 is hydrogen, hydroxy, oxo, halo, nitro, cyano,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy, trihalomethyl,
trihalomethoxy, NR.sup.11R.sup.12, arylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; R.sup.9 and R.sup.10
independently are hydrogen, halo, oxo, hydroxy, C.sub.1-C.sub.6alkyl,
aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylalkyl; R.sup.11 and
R.sup.12 independently are hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyl-carboxyC.sub.1-C.sub.6alkyl; or R.sup.11 and
R.sup.12 together with the nitrogen to which they are attached, are
forming a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur, the
ring system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkyl-carbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy; or a salt thereof with a
pharmaceutically acceptable acid or base, or any optical isomer or
mixture of optical isomers, including a racemic mixture, or any
tautomeric forms.

[0934] In another embodiment of the present invention, in formula (V) and
(Va) R.sup.1 is hydrogen, C.sub.1-C.sub.8alkyl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, arylSO.sub.2, hetarylSO.sub.2,
arylC.sub.1-C.sub.6alkylSO.sub.2 or hetarylC.sub.1-C.sub.6alkylSO.sub.2
all of which is optionally substituted with one or more R.sup.8.

[0935] In another embodiment of the present invention, in formula (V) and
(Va) R.sup.1 is hydrogen, C.sub.1-C.sub.8alkyl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl all of which is optionally substituted with
one or more R.sup.8.

[0936] In another embodiment of the present invention, in formula (V) and
(Va) R.sup.1 is arylSO.sub.2, hetarylSO.sub.2,
arylC.sub.1-C.sub.6alkylSO.sub.2 or hetarylC.sub.1-C.sub.6alkylSO.sub.2
all of which is optionally substituted with one or more R.sup.8.

[0937] In another embodiment of the present invention, in formula (V) and
(Va) R.sup.2 is hydrogen.

[0938] In another embodiment of the present invention, in formula (V) and
(Va) R.sup.3 is hydrogen and R.sup.4 is C(O)NR.sup.7R.sup.8.

[0939] In another embodiment of the present invention, in formula (V) and
(Va) R.sup.3 is C(O)NR.sup.7R.sup.8 and R.sup.4 is hydrogen.

[0940] In another embodiment of the present invention, in formula (V) and
(Va) R.sup.5 is hydrogen.

[0941] In another embodiment of the present invention, in formula (V)
R.sup.6 is hydrogen, NR.sup.12R.sup.13, C.sub.1-C.sub.6alkyl, aryl or
hetaryl wherein the alkyl, aryl and hetaryl independently are substituted
with one or more R.sup.9.

[0942] In another embodiment of the present invention, in formula (V) and
(Va) R.sup.7 and R.sup.8 independently are C.sub.1-C.sub.8alkyl or
C.sub.3-C.sub.10cycloalkyl, wherein the alkyl and cycloalkyl groups
independently are optionally substituted with one or more of R.sup.10.

[0943] In another embodiment of the present invention, in formula (V) and
(Va) R.sup.7 and R.sup.8 together with the nitrogen to which they are
attached, are forming a saturated or partially saturated bicyclic or
tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to
2 additional heteroatoms selected from nitrogen or oxygen, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.11.

[0945] In another embodiment of the present invention, in formula (V) and
(Va) R.sup.10 and R.sup.11 independently are hydrogen, halo, oxo,
hydroxy, C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or
hetarylalkyl.

[0946] In another embodiment of the present invention, in formula (V) and
(Va) R.sup.11 and R.sup.12 together with the nitrogen to which they are
attached, are forming a saturated or partially saturated cyclic, bicyclic
or tricyclic ring system containing from 4 to 10 carbon atoms and from 0
to 2 additional heteroatoms selected from nitrogen or oxygen, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkyl-carbonyl, hetarylC.sub.1-C.sub.6alkylarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy.

[0947] In another embodiment of the present invention the compound of the
general formulas (V) and (Va), or a prodrug thereof is
1H-Benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; or a salt
thereof with a pharmaceutically acceptable acid or base, or any optical
isomer or mixture of optical isomers, including a racemic mixture, or any
tautomeric forms.

[0948] In yet another embodiment of the present invention the compounds of
the general formulas (V) and (Va), or a prodrug thereof is selected from
the group consisting of: [0949] 1-Benzyl-1H-benzoimidazole-5-carboxylic
acid cyclohexyl-methyl-amide; [0950]
(1H-Benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-me-
thanone; or a salt thereof with a pharmaceutically acceptable acid or
base, or any optical isomer or mixture of optical isomers, including a
racemic mixture, or any tautomeric forms.

[0964] In another embodiment, the present invention is concerned with
compounds or prodrugs thereof of the general formula (VI) wherein X is
oxygen or (CR.sup.1R.sup.2).sub.n; R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 independently are hydrogen, C.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylC.sub.1-C.sub.6alkyl
optionally substituted with one or more R.sup.8 independently; or
R.sup.1 and either R.sup.3 or R.sup.4 together are forming a saturated or
partially saturated ring system containing from 4 to 8 carbon atoms, the
ring system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, hydroxy, oxo, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl; or R.sup.1 and
either R.sup.3 or R.sup.4 together with the single bond are forming a
carbon-carbon double bond; R.sup.5 is C.sub.1-C.sub.8alkyl optionally
substituted with one or more of R.sup.9; R.sup.6 is
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the alkyl,
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.9; or R.sup.5 and R.sup.6 together
with the nitrogen to which they are attached, are forming a saturated or
partially saturated cyclic, bicyclic or tricyclic ring system containing
from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected
from nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.10;
R.sup.7 is hydrogen, halo, nitro, NR.sup.12R.sup.13, cyano,
trihalomethyl, C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, hetaryloxy or
hetarylC.sub.1-C.sub.6-alkyloxy optionally substituted with one or more
R.sup.11 independently; R.sup.8 and R.sup.9 independently are hydrogen,
hydroxy, oxo, halo, nitro, cyano, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6-alkyloxy, trihalomethyl, trihalomethoxy,
NR.sup.12R.sup.13, arylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 is hydrogen,
C.sub.1-C.sub.8alkyl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy; R.sup.11 is
hydrogen, halo, hydroxy, oxo, nitro, cyano, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.6alkyloxy, aryloxy or hetaryloxy; R.sup.12 and R.sup.13
independently are hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, C.sub.1-C.sub.6alkylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6alkyloxycarbonyl; or R.sup.12 and R.sup.13 are together
with the nitrogen to which they are attached, are forming a saturated or
partially saturated cyclic, bicyclic or tricyclic ring system containing
from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected
from nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or arylC.sub.1-6alkylcarboxy;
[0965] n is 1 or 2; or a salt thereof with a pharmaceutically acceptable
acid or base, or any optical isomer or mixture of optical isomers,
including a racemic mixture, a prodrug thereof, or any tautomeric forms.

[0966] In one embodiment of the present invention, in formula (VI) X is
(CR.sup.1R.sup.2).sub.n, wherein R.sup.1, R.sup.2 and n are as defined
above.

[0967] In another embodiment of the present invention, in formula (VI) n
is 1.

[0968] In another embodiment of the present invention, in formula (VI) X
is oxygen.

[0969] In another embodiment of the present invention, in formula (VI)
R.sup.1, R.sup.2, R.sup.3, and R.sup.4 independently are hydrogen,
C.sub.1-C.sub.6alkyl or arylC.sub.1-C.sub.6alkyl, optionally substituted
with one or more R.sup.8.

[0970] In another embodiment of the present invention, in formula (VI)
R.sup.1 and either R.sup.3 or R.sup.4 together with the single bond are
forming a carbon-carbon double bond.

[0971] In another embodiment of the present invention, in formula (VI)
R.sup.5 is C.sub.1-C.sub.8alkyl optionally substituted with one or more
of R.sup.9.

[0972] In another embodiment of the present invention, in formula (VI)
R.sup.6 is C.sub.3-C.sub.10cycloalkyl or C.sub.3-C.sub.10hetcycloalkyl
each of which is optionally substituted with one or more of R.sup.9.

[0973] In another embodiment of the present invention, in formula (VI)
R.sup.6 is C.sub.3-C.sub.10cycloalkyl optionally substituted with one or
more of R.sup.9.

[0974] In another embodiment of the present invention, in formula (VI)
R.sup.5 and R.sup.6 together with the nitrogen to which they are
attached, are forming a saturated or partially saturated cyclic, bicyclic
or tricyclic ring system containing from 6 to 10 carbon atoms and from 0
to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur,
the ring system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.10.

[0975] In another embodiment of the present invention, in formula (VI)
R.sup.7 is hydrogen, halo, NR.sup.12R.sup.13, trihalomethyl,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetaryloxy optionally substituted with one or more R.sup.11
independently.

[0977] In another embodiment of the present invention, in formula (VI)
R.sup.10 is hydrogen or C.sub.1-C.sub.8alkyl.

[0978] In yet another embodiment of the present invention, in formula (VI)
the bicyclic ring system is 6-aza-bicyclo[3.2.1]octane optionally
substituted with one or more of C.sub.1-C.sub.6alkyl.

[0979] In yet another embodiment of the present invention, in formula (VI)
the bicyclic ring system is 1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane.

[0980] In yet another embodiment of the present invention a compound of
the general formula (VI) or a prodrug thereof is
2,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexylmethyl-amide or a salt thereof with a pharmaceutically
acceptable acid or base, or any optical isomer or mixture of optical
isomers, including a racemic mixture, or any tautomeric forms.

[1004] In another embodiment, the present invention is concerned with
compounds or prodrugs thereof of the general formula (VII) wherein
R.sup.1 is hydrogen, C.sub.1-C.sub.8alkyl, hetaryl,
arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl optionally
substituted with one or more R.sup.9; R.sup.2, R.sup.3, R.sup.4, R.sup.5
and R.sup.6 independently are hydrogen, halo, nitro, cyano,
trihalomethyl, carboxy, N(R.sup.12R.sup.13), C(O)NR.sup.7R.sup.8,
C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, N(R.sup.12R.sup.13)C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
aryl, arylC.sub.1-C.sub.6alkyl, aryloxy, aryloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy,
arylC.sub.1-C.sub.6alkylcarboxy, hetaryl, hetarylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyloxy, hetaryloxyC.sub.1-C.sub.6alkyl or
hetarylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl wherein the alkyl,
aryl, arylalkyl, hetaryl and hetarylalkyl groups independently are
substituted with one or more R.sup.9; R.sup.7 is hydrogen or
C.sub.1-C.sub.8alkyl optionally substituted with one or more of R.sup.10;
R.sup.8 is C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the cycloalkyl
and hetcycloalkyl groups independently are optionally substituted with
one or more of R.sup.10; or R.sup.7 and R.sup.8 together with the
nitrogen to which they are attached, are forming a saturated or partially
saturated cyclic, bicyclic or tricyclic ring system containing from 4 to
10 carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen or oxygen, the ring system optionally being substituted with at
least one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyl-oxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.11;
R.sup.9 is hydrogen, hydroxy, oxo, halo, nitro, cyano,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy, trihalomethyl,
trihalomethoxy, NR.sup.12R.sup.13, arylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 and R.sup.11
independently are hydrogen, halo, oxo, hydroxy, C.sub.1-C.sub.6alkyl,
aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylalkyl; R.sup.12 and
R.sup.13 independently are hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, C.sub.3-C.sub.10cycloalkylcarbonyl,
C.sub.3-C.sub.10hetcycloalkylcarbonyl or
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkylcarbonyl wherein the alkyl
and aryl groups independently are optionally substituted with one or more
of R.sup.11, wherein R.sup.11 is as defined above; or R.sup.12 and
R.sup.13 together with the nitrogen to which they are attached, are
forming a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur, the
ring system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy; or a salt thereof with a
pharmaceutically acceptable acid or base, or any optical isomer or
mixture of optical isomers, including a racemic mixture, or any
tautomeric forms.

[1005] In another embodiment, the present invention is concerned with
compounds or prodrugs thereof of the general formula (VII) wherein

R.sup.1 is hydrogen, C.sub.1-C.sub.8alkyl, hetaryl,
arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl optionally
substituted with one or more R.sup.9;

R.sup.7 is C.sub.1-C.sub.8alkyl optionally substituted with one or more
of R.sup.10;

R.sup.8 is C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the cycloalkyl
and hetcycloalkyl groups independently are optionally substituted with
one or more of R.sup.10; or

[1007] R.sup.7 and R.sup.8 together with the nitrogen to which they are
attached, are forming a saturated or partially saturated cyclic, bicyclic
or tricyclic ring system containing from 6 to 10 carbon atoms and from 0
to 2 additional heteroatoms selected from nitrogen or oxygen, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyl-oxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.11;

[1010] R.sup.12 and R.sup.13 together with the nitrogen to which they are
attached, are forming a saturated or partially saturated cyclic, bicyclic
or tricyclic ring system containing from 4 to 10 carbon atoms and from 0
to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur,
the ring system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy; or

a salt thereof with a pharmaceutically acceptable acid or base, or any
optical isomer or mixture of optical isomers, including a racemic
mixture, or any tautomeric forms.

[1011] In another embodiment, the present invention, in formula (VII)
R.sup.2 is C(O)NR.sup.7R.sup.8 and R.sup.3 R.sup.4 and R.sup.5 are
hydrogen, wherein R.sup.7 and R.sup.8 are as defined above.

[1012] In another embodiment, the present invention, in formula (VII)
R.sup.3 is C(O)NR.sup.7R.sup.8 and R.sup.2 R.sup.4 and R.sup.5 are
hydrogen, wherein R.sup.7 and R.sup.8 are as defined above.

[1013] In another embodiment, the present invention, in formula (VII)
R.sup.4 is C(O)NR.sup.7R.sup.8 and R.sup.2 R.sup.3 and R.sup.5 are
hydrogen, wherein R.sup.7 and R.sup.8 are as defined above.

[1014] In another embodiment, the present invention, in formula (VII)
R.sup.5 is C(O)NR.sup.7R.sup.8 and R.sup.2 R.sup.3 and R.sup.4 are
hydrogen, wherein R.sup.7 and R.sup.8 are as defined above.

[1015] In another embodiment, the present invention, in formula (VII)
R.sup.6 is C(O)NR.sup.7R.sup.8, wherein R.sup.7 and R.sup.8 are as
defined above.

[1016] In another embodiment, the present invention, in formula (VII)
R.sup.3 is C(O)NR.sup.7R.sup.8 and R.sup.4 is hydrogen, wherein R.sup.7
and R.sup.8 are as defined above.

[1017] In another embodiment, the present invention, in formula (VII)
R.sup.3 is hydrogen and R.sup.4 is C(O)NR.sup.7R.sup.8, wherein R.sup.7
and R.sup.8 are as defined above.

[1018] In another embodiment, the present invention, in formula (VII)
R.sup.8 is C.sub.3-C.sub.10cycloalkyl or C.sub.3-C.sub.10hetcycloalkyl,
each of which is optionally substituted with one or more of R.sup.10,
wherein R.sup.10 is as defined above.

[1019] In another embodiment, the present invention, in formula (VII)
R.sup.7 and R.sup.8 together with the nitrogen to which they are
attached, are forming a saturated or partially saturated bicyclic or
tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to
2 additional heteroatoms selected from nitrogen or oxygen, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyl-oxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.11,
wherein R.sup.11 is as defined above.

[1020] In a further embodiment of the present invention, in formula (VII)
the bicyclic ring system is 6-aza-bicyclo[3.2.1]octane optionally
substituted with one or more C.sub.1-C.sub.6alkyl.

[1021] In yet a further embodiment of the present invention, in formula
(VII) the bicyclic ring system is
1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane.

[1022] In another embodiment of the present invention the compounds of the
general formula (VII) or a prodrug thereof is selected from the group
consisting of: [1023]
(1H-Indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
[1024] 1H-Indole-6-carboxylic acid cyclohexyl-methyl-amide; or a salt
thereof with a pharmaceutically acceptable acid or base, or any optical
isomer or mixture of optical isomers, including a racemic mixture, or any
tautomeric forms.

[1025] In another embodiment of the present invention, the compounds or
prodrugs thereof of the general formula (VII) are selected from the group
consisting of the compounds of examples 3 through 20 as described under
EXAMPLES, COMPOUNDS OF GENERAL FORMULA (VII).

[1026] In another embodiment, the present invention is concerned with
compounds or prodrugs thereof of the general formula (VIII) wherein X
is NR.sup.4, S or O; R.sup.1 and R.sup.2 independently are hydrogen,
halo, cyano, trihalomethyl, C.sub.1-C.sub.6alkyl or
C.sub.1-C.sub.6alkyloxy, wherein the alkyl groups independently are
optionally substituted with one or more of R.sup.7; R.sup.3 is hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylthio, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylalkyl, wherein the alkyl,
cycloalkyl, aryl, hetaryl and hetarylalkyl groups independently are
optionally substituted with one or more of R.sup.7; R.sup.4 is hydrogen,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryl,
hetaryl, hetarylC.sub.1-C.sub.6alkyl, arylC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cyclo-alkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl wherein the alkyl, aryl,
hetaryl, cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.7; R.sup.5 is hydrogen, and
R.sup.6 is adamantyl optionally substituted with hydroxy,
C.sub.1-C.sub.6alkyloxy, aryl, arylC.sub.1-C.sub.6alkyl, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, hetaryl, hetaryloxy or
hetarylC.sub.1-C.sub.6alkyloxy wherein the alkyl, aryl and hetaryl groups
independently are optionally substituted with one or more of R.sup.7; or
R.sup.5 and R.sup.6 are together with the nitrogen to which they are
attached, forming a saturated or partially saturated cyclic, bicyclic or
tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to
2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the
ring system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylalkyl, hydroxy, oxo, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.7;
R.sup.7 are independently hydrogen, halo, hydroxy, oxo, nitro,
NR.sup.9R.sup.10, cyano, COOR.sup.8, CONR.sup.9R.sup.10,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, hetaryloxy or
hetarylC.sub.1-C.sub.6alkyloxy; R.sup.8 is hydrogen,
C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl, hetarylalkyl,
wherein the alkyl, aryl and hetarylalkyl groups independently are
optionally substituted with one or more of R.sup.7; R.sup.9 and R.sup.10
independently are hydrogen, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the alkyl,
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.7; or R.sup.9 and R.sup.10
together with the nitrogen to which they are attached, are forming a
saturated or partially saturated bicyclic or tricyclic ring system
containing from 4 to 10 carbon atoms and from 0 to 2 additional
heteroatoms selected from nitrogen or oxygen, the ring system optionally
being substituted with at least one of C.sub.1-C.sub.8alkyl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.11;
R.sup.11 is hydrogen, halo, oxo, hydroxy, C.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylalkyl; a salt thereof with a
pharmaceutically acceptable acid or base, or any optical isomer or
mixture of optical isomers, including a racemic mixture, or any
tautomeric forms.

[1027] In the definitions of R.sup.4, in the above formula (VIII),
hetcycloalkyl cannot be 7-aza[2,2,1]bicycloheptane.

[1028] In another embodiment, the present invention is concerned with
compounds or prodrugs thereof of the above general formula (VIII) wherein

X is NR.sup.4, S or O;

R.sup.1 and R.sup.2 independently are hydrogen, halo, cyano,
trihalomethyl, C.sub.1-C.sub.6alkyl or C.sub.1-C.sub.6alkyloxy, wherein
the alkyl groups independently are optionally substituted with one or
more of R.sup.7;

[1029] R.sup.3 is hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkylthio, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or
hetarylalkyl, wherein the alkyl, cycloalkyl, aryl, hetaryl and
hetarylalkyl groups independently are optionally substituted with one or
more of R.sup.7;

[1031] R.sup.5 is hydrogen, and R.sup.6 is adamantyl optionally
substituted with hydroxy, C.sub.1-C.sub.6alkyloxy, aryl,
arylC.sub.1-C.sub.6alkyl, aryloxy, arylC.sub.1-C.sub.6alkyloxy, hetaryl,
hetaryloxy or hetarylC.sub.1-C.sub.6alkyloxy wherein the alkyl, aryl and
hetaryl groups independently are optionally substituted with one or more
of R.sup.7; or

[1032] R.sup.5 and R.sup.6 are together with the nitrogen to which they
are attached, forming a saturated or partially saturated cyclic, bicyclic
or tricyclic ring system containing from 5 to 10 carbon atoms and from 0
to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur,
the ring system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylalkyl, hydroxy, oxo, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.7;

R.sup.8 is hydrogen, C.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetarylalkyl, wherein the alkyl, aryl and
hetarylalkyl groups independently are optionally substituted with one or
more of R.sup.7; or

a salt thereof with a pharmaceutically acceptable acid or base, or any
optical isomer or mixture of optical isomers, including a racemic
mixture, or any tautomeric forms.

[1033] In one embodiment of the present invention, in formula (VIII) X is
NR.sup.4 or S wherein R.sup.4 is defined as above.

[1034] In another embodiment of the present invention, in formula (VIII) X
is O.

[1035] In another embodiment of the present invention, in formula (VIII) X
is S.

[1036] In another embodiment of the present invention, in formula (VIII)
is NR.sup.4 wherein R.sup.4 is defined as above.

[1037] In another embodiment of the present invention, in formula (VIII)
R.sup.1 and R.sup.2 independently are hydrogen, halo, trihalomethyl or
C.sub.1-C.sub.6alkyl, wherein the alkyl groups independently are
optionally substituted with one or more of R.sup.7.

[1038] In another embodiment of the present invention, in formula (VIII)
R.sup.3 is hydrogen, C.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylalkyl, wherein the alkyl,
cycloalkyl, aryl, hetaryl and hetarylalkyl groups independently are
optionally substituted with one or more of R.sup.7.

[1039] In another embodiment of the present invention, in formula (VIII)
R.sup.4 is hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, arylC.sub.1-C.sub.6alkyl, wherein the alkyl,
aryl, hetaryl, groups independently are optionally substituted with one
or more of R.sup.7.

[1040] In another embodiment of the present invention, in formula (VIII)
R.sup.5 and R.sup.6 are together with the nitrogen to which they are
attached, forming a saturated or partially saturated cyclic, bicyclic or
tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to
2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the
ring system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylalkyl, hydroxy, oxo, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl and aryl groups
independently are optionally substituted with one or more of R.sup.7.

[1041] In yet another embodiment of the present invention, in formula
(VIII) R.sup.5 and R.sup.6, together with the nitrogen to which they are
attached, are azepane, azocane, 6-aza-bicyclo[3.2.1]octane,
8-aza-bicyclo[3.2.1]octane, 3-aza-bicyclo[3.2.1]octane,
2-aza-bicyclo[3.2.1]octane, 3-oxa-6-aza-bicyclo[3.2.1]octane,
6-aza-bicyclo[3.2.2]nonane, 3-aza-bicyclo[3.2.2]nonane,
4-aza-tricyclo[4.3.1.1.sup.3,8]undecane.

[1042] In another embodiment of the present invention the compounds of the
general formulas (VIII) or a prodrug thereof is selected from the group
consisting of: [1043]
(4-Methyl-2-phenyl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-
-6-yl)-methanone; [1044]
(2,4-Dimethyl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl-
)-methanone; [1045]
(4-Methyl-2-pyrazin-2-yl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2-
.1]oct-6-yl)-methanone; [1046]
[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-(1,3,3-trimethyl-6-a-
za-bicyclo[3.2.1]oct-6-yl)-methanone; [1047]
(3-Aza-bicyclo[3.2.2]non-3-yl)-(2,4-dimethyl-thiazol-5-yl)-methanone;
[1048] (1H-Imidazol-4-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)--
methanone; [1049]
(3-Aza-bicyclo[3.2.2]non-3-yl)-(4-methyl-2-phenyl-thiazol-5-yl)-methanone-
; [1050] 2,4-Dimethyl-thiazole-5-carboxylic acid cycloheptylamide;
[1051] Azepan-1-yl-(2,4-dimethyl-thiazol-5-yl)-methanone; [1052]
2,4-Dimethyl-thiazole-5-carboxylic acid adamantan-1-ylamide; [1053]
(3-Aza-bicyclo[3.2.2]non-3-yl)-(1H-imidazol-4-yl)-methanone; [1054]
2,4-Dimethyl-thiazole-5-carboxylic acid (3-hydroxy-adamantan-1-yl)-amide;
or a salt thereof with a pharmaceutically acceptable acid or base, or
any optical isomer or mixture of optical isomers, including a racemic
mixture, or any tautomeric forms.

[1055] In another embodiment of the present invention the compounds of the
general formulas (VIII) or a prodrug thereof is selected from the group
consisting of: [1056]
(1-Methyl-1H-imidazol-4-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl-
)-methanone; [1057]
[1-(6-Methyl-pyridin-2-yl)-1H-imidazol-4-yl]-(1,3,3-trimethyl-6-aza-bicyc-
lo[3.2.1]oct-6-yl)-methanone; [1058]
[1-(4-Chloro-benzyl)-5-methyl-1H-imidazol-4-yl]-(1,3,3-trimethyl-6-aza-bi-
cyclo[3.2.1]oct-6-yl)-methanone; or a salt thereof with a
pharmaceutically acceptable acid or base, or any optical isomer or
mixture of optical isomers, including a racemic mixture, or any
tautomeric forms.

[1059] The compounds of the present invention have asymmetric centers and
may occur as racemates, racemic mixtures, and as individual enantiomers
or diastereoisomers, with all isomeric forms being included in the
present invention as well as mixtures thereof.

[1063] The stereoisomers of the compounds forming part of this invention
may be prepared by using reactants in their single enantiomeric form in
the process wherever possible or by conducting the reaction in the
presence of reagents or catalysts in their single enantiomer form or by
resolving the mixture of stereoisomers by conventional methods. Some of
the preferred methods include use of microbial resolution, enzymatic
resolution, resolving the diastereomeric salts formed with chiral acids
such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid,
and the like wherever applicable or chiral bases such as brucine, (R)- or
(S)-phenylethylamine, cinchona alkaloids and their derivatives and the
like. Commonly used methods are compiled by Jaques et al. in
"Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981). More
specifically the compound of the present invention may be converted to a
1:1 mixture of diastereomeric amides by treating with chiral amines,
aminoacids, aminoalcohols derived from aminoacids; conventional reaction
conditions may be employed to convert acid into an amide; the
diastereomers may be separated either by fractional crystallization or
chromatography and the stereoisomers of compound of formula I may be
prepared by hydrolysing the pure diastereomeric amide.

[1064] Various polymorphs of the compounds forming part of this invention
may be prepared by crystallization of said compounds under different
conditions. For example, using different solvents commonly used or their
mixtures for recrystallization; crystallizations at different
temperatures; various modes of cooling, ranging from very fast to very
slow cooling during crystallizations. Polymorphs may also be obtained by
heating or melting the compound followed by gradual or fast cooling. The
presence of polymorphs may be determined by solid probe nmr spectroscopy,
ir spectroscopy, differential scanning calorimetry, powder X-ray
diffraction or such other techniques.

[1065] The invention also encompasses prodrugs of the present compounds,
which on administration undergo chemical conversion by metabolic
processes before becoming active pharmacological substances. In general,
such prodrugs will be functional derivatives of the present compounds,
which are readily convertible in vivo into the required compound of the
present invention. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for example,
in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

[1066] It is a well known problem in drug discovery that compounds, such
as enzyme inhibitors, may be very potent and selective in biochemical
assays, yet be inactive in vivo. This lack of so-called bioavailability
may be ascribed to a number of different factors such as lack of or poor
absorption in the gut, first pass metabolism in the liver and/or poor
uptake in cells. Although the factors determining bioavailability are not
completely understood, there are many examples in the scientific
literature--well known to those skilled in the art--of how to modify
compounds, which are potent and selective in biochemical assays but show
low or no activity in vivo, into drugs that are biologically active.

[1067] It is within the scope of the invention to modify the compounds of
the present invention, termed the `original compound`, by attaching
chemical groups that will improve the bioavailability of said compounds
in such a way that the uptake in cells or mammals is facilitated.

[1068] Examples of said modifications, which are not intended in any way
to limit the scope of the invention, include changing of one or more
carboxy groups to esters (for instance methyl esters, ethyl esters,
tert-butyl, acetoxymethyl, pivaloyloxymethyl esters or other
acyloxymethyl esters). Compounds of the invention, original compounds,
such modified by attaching chemical groups are termed `modified
compounds`.

[1069] The invention also encompasses active metabolites of the present
compounds.

[1070] The compounds according to the invention alter, and more
specifically, reduce the level of active intracellular glucocorticoid and
are accordingly useful for the treatment, prevention and/or prophylaxis
of disorders and diseases in which such a modulation or reduction is
beneficial.

[1073] Accordingly, in a further aspect the invention relates to a
compound according to the invention for use as a pharmaceutical
composition.

[1074] The invention also relates to pharmaceutical compositions
comprising, as an active ingredient, at least one compound according to
the invention together with one or more pharmaceutically acceptable
carriers or diluents.

[1075] The pharmaceutical composition is preferably in unit dosage form,
comprising from about 0.05 mg/day to about 2000 mg/day, preferably from
about 1 mg/day to about 500 mg/day of a compound according to the
invention.

[1076] In another embodiment, the patient is treated with a compound
according to the invention for at least about 1 week, for at least about
2 weeks, for at least about 4 weeks, for at least about 2 months or for
at least about 4 months.

[1077] In yet another embodiment, the pharmaceutical composition is for
oral, nasal, transdermal, pulmonal or parenteral administration.

[1078] Furthermore, the invention relates to the use of a compound
according to the invention for the preparation of a pharmaceutical
composition for the treatment, prevention and/or prophylaxis of disorders
and diseases wherein a modulation or an inhibition of the activity of
11.beta.HSD1 is beneficial.

[1079] The invention also relates to a method for the treatment,
prevention and/or prophylaxis of disorders and diseases wherein a
modulation or an inhibition of the activity of 11.beta.HSD1 is
beneficial, the method comprising administering to a subject in need
thereof an effective amount of a compound according to the invention.

[1080] In a preferred embodiment of the invention the present compounds
are used for the preparation of a medicament for the treatment,
prevention and/or prophylaxis of any diseases and conditions that are
influenced by intracellular glucocorticoid levels as mentioned above.

[1081] Thus, in a preferred embodiment of the invention the present
compounds are used for the preparation of a medicament for the treatment,
prevention and/or prophylaxis of conditions and disorders where a
decreased level of active intracellular glucocorticoid is desirable, such
as the conditions and diseases mentioned above.

[1082] In yet a preferred embodiment of the invention the present
compounds are used for the preparation of a medicament for the treatment,
prevention and/or prophylaxis of the metabolic syndrome including insulin
resistance, dyslipidemia, hypertension and obesity.

[1083] In yet another preferred embodiment of the invention the present
compounds are used for the preparation of a medicament for the treatment,
prevention and/or prophylaxis of type 2 diabetes, impaired glucose
tolerance (IGT), impaired fasting glucose (IFG).

[1084] In yet another preferred embodiment of the invention the present
compounds are used for the preparation of a pharmaceutical composition
for the delaying or prevention of the progression from IGT to type 2
diabetes.

[1085] In yet another preferred embodiment of the invention the present
compounds are used for the preparation of a pharmaceutical composition
for the delaying or prevention of the progression of the metabolic
syndrome into type 2 diabetes.

[1086] In still another preferred embodiment of the invention the present
compounds are used for the preparation of a pharmaceutical composition
for the treatment, prevention and/or prophylaxis of diabetic late
complications including cardiovascular diseases; arteriosclerosis;
atherosclerosis.

[1087] In a further preferred embodiment of the invention the present
compounds are used for the preparation of a pharmaceutical composition
for the treatment, prevention and/or prophylaxis of neurodegenerative and
psychiatric disorders.

[1088] In yet a further preferred embodiment of the invention the present
compounds are used for the preparation of a pharmaceutical composition
for the treatment, prevention and/or prophylaxis of adverse effects of
glucocorticoid receptor agonist treatment or therapy.

[1089] In another embodiment of the present invention, the route of
administration may be any route which effectively transports a compound
according to the invention to the appropriate or desired site of action,
such as oral, nasal, buccal, transdermal, pulmonal, or parenteral.

[1090] In still a further aspect of the invention the present compounds
are administered in combination with one or more further active
substances in any suitable ratios. Such further active substances may
e.g. be selected from antiobesity agents, antidiabetics, agents modifying
the lipid metabolism, antihypertensive agents, glucocorticoid receptor
agonists, agents for the treatment and/or prevention of complications
resulting from or associated with diabetes and agents for the treatment
and/or prevention of complications and disorders resulting from or
associated with obesity.

[1091] Thus, in a further aspect of the invention the present compounds
may be administered in combination with one or more antiobesity agents or
appetite regulating agents.

[1096] In one embodiment, the present compounds are administered in
combination with insulin or an insulin analogue or derivative, such as
N.sup..epsilon.B29-tetradecanoyl des (B30) human insulin, Asp.sup.B28
human insulin, Lys.sup.B28 Pro.sup.B29 human insulin, Lantus.RTM., or a
mix-preparation comprising one or more of these.

[1097] In a further embodiment the present compounds are administered in
combination with a sulphonylurea e.g. tolbutamide, glibenclamide,
glipizide or glicazide.

[1098] In another embodiment the present compounds are administered in
combination with a biguanide e.g. metformin.

[1099] In yet another embodiment the present compounds are administered in
combination with a meglitinide e.g. repaglinide or senaglinide.

[1100] In still another embodiment the present compounds are administered
in combination with a thiazolidinedione e.g. troglitazone, ciglitazone,
pioglitazone, rosiglitazone or compounds disclosed in WO 97/41097 such as
5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl-methyl]th-
iazolidine-2,4-dione or a pharmaceutically acceptable salt thereof,
preferably the potassium salt.

[1101] In yet another embodiment the present compounds may be administered
in combination with the insulin sensitizers disclosed in WO 99/19313 such
as (-)3-[4-[2-Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid or a
pharmaceutically acceptable salts thereof, preferably the arginine salt.

[1102] In a further embodiment the present compounds are administered in
combination with an .alpha.-glucosidase inhibitor e.g. miglitol or
acarbose.

[1103] In another embodiment the present compounds are administered in
combination with an agent acting on the ATP-dependent potassium channel
of the .beta.-cells e.g. tolbutamide, glibenclamide, glipizide, glicazide
or repaglinide.

[1104] Furthermore, the present compounds may be administered in
combination with nateglinide.

[1106] In a further embodiment the present compounds are administered in
combination with more than one of the above-mentioned compounds e.g. in
combination with a sulphonylurea and metformin, a sulphonylurea and
acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin
and metformin, insulin, insulin and lovastatin, etc.

[1110] It should be understood that any suitable combination of the
compounds according to the invention with one or more of the
above-mentioned compounds and optionally one or more further
pharmacologically active substances are considered to be within the scope
of the present invention.

Pharmaceutical Compositions

[1111] The compounds of the present invention may be administered alone or
in combination with pharmaceutically acceptable carriers or excipients,
in either single or multiple doses. The pharmaceutical compositions
according to the invention may be formulated with pharmaceutically
acceptable carriers or diluents as well as any other known adjuvants and
excipients in accordance with conventional techniques such as those
disclosed in Remington: The Science and Practice of Pharmacy, 19.sup.th
Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

[1112] The pharmaceutical compositions may be specifically formulated for
administration by any suitable route such as the oral, rectal, nasal,
pulmonary, topical (including buccal and sublingual), transdermal,
intracisternal, intraperitoneal, vaginal and parenteral (including
subcutaneous, intramuscular, intrathecal, intravenous and intradermal)
route, the oral route being preferred. It will be appreciated that the
preferred route will depend on the general condition and age of the
subject to be treated, the nature of the condition to be treated and the
active ingredient chosen.

[1113] Pharmaceutical compositions for oral administration include solid
dosage forms such as hard or soft capsules, tablets, troches, dragees,
pills, lozenges, powders and granules. Where appropriate, they can be
prepared with coatings such as enteric coatings or they can be formulated
so as to provide controlled release of the active ingredient such as
sustained or prolonged release according to methods well-known in the
art.

[1115] Pharmaceutical compositions for parenteral administration include
sterile aqueous and non-aqueous injectable solutions, dispersions,
suspensions or emulsions as well as sterile powders to be reconstituted
in sterile injectable solutions or dispersions prior to use. Depot
injectable formulations are also contemplated as being within the scope
of the present invention.

[1117] A typical oral dosage is in the range of from about 0.001 to about
100 mg/kg body weight per day, preferably from about 0.01 to about 50
mg/kg body weight per day, and more preferred from about 0.05 to about 10
mg/kg body weight per day administered in one or more dosages such as 1
to 3 dosages. The exact dosage will depend upon the frequency and mode of
administration, the sex, age, weight and general condition of the subject
treated, the nature and severity of the condition treated and any
concomitant diseases to be treated and other factors evident to those
skilled in the art.

[1118] The formulations may conveniently be presented in unit dosage form
by methods known to those skilled in the art. A typical unit dosage form
for oral administration one or more times per day such as 1 to 3 times
per day may contain from 0.05 to about 2000 mg, e.g. from about 0.1 to
about 1000 mg, from about 0.5 mg to about 500 mg., from about 1 mg to
about 200 mg, e.g. about 100 mg.

[1119] For parenteral routes, such as intravenous, intrathecal,
intramuscular and similar administration, typically doses are in the
order of about half the dose employed for oral administration.

[1120] The compounds of this invention are generally utilized as the free
substance or as a pharmaceutically acceptable salt thereof. Examples are
an acid addition salt of a compound having the utility of a free base and
a base addition salt of a compound having the utility of a free acid. The
term "pharmaceutically acceptable salts" refers to non-toxic salts of the
compounds for use according to the present invention which are generally
prepared by reacting the free base with a suitable organic or inorganic
acid or by reacting the acid with a suitable organic or inorganic base.
When a compound for use according to the present invention, contains a
free base such salts are prepared in a conventional manner by treating a
solution or suspension of the compound with a chemical equivalent of a
pharmaceutically acceptable acid. When a compounds for use according to
the present invention, contains a free acid such salts are prepared in a
conventional manner by treating a solution or suspension of the compound
with a chemical equivalent of a pharmaceutically acceptable base.
Physiologically acceptable salts of a compound with a hydroxy group
include the anion of said compound in combination with a suitable cation
such as sodium or ammonium ion. Other salts which are not
pharmaceutically acceptable may be useful in the preparation of compounds
for use according to the present invention and these form a further
aspect of the present invention.

[1121] For parenteral administration, solutions of the present compounds
in sterile aqueous solution, aqueous propylene glycol or sesame or peanut
oil may be employed. Such aqueous solutions should be suitable buffered
if necessary and the liquid diluent first rendered isotonic with
sufficient saline or glucose. The aqueous solutions are particularly
suitable for intravenous, intramuscular, subcutaneous and intraperitoneal
administration. The sterile aqueous media employed are all readily
available by standard techniques known to those skilled in the art.

[1123] The pharmaceutical compositions formed by combining the compounds
of the invention and the pharmaceutically acceptable carriers are then
readily administered in a variety of dosage forms suitable for the
disclosed routes of administration. The formulations may conveniently be
presented in unit dosage form by methods known in the art of pharmacy.

[1124] Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules or
tablets, each containing a predetermined amount of the active ingredient,
and which may include a suitable excipient. These formulations may be in
the form of powder or granules, as a solution or suspension in an aqueous
or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid
emulsion.

[1125] Compositions intended for oral use may be prepared according to any
known method, and such compositions may contain one or more agents
selected from the group consisting of sweetening agents, flavouring
agents, colouring agents, and preserving agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets may contain
the active ingredient in admixture with non-toxic
pharmaceutically-acceptable excipients which are suitable for the
manufacture of tablets. These excipients may be for example, inert
diluents, such as calcium carbonate, sodium carbonate, lactose, calcium
phosphate or sodium phosphate; granulating and disintegrating agents, for
example corn starch or alginic acid; binding agents, for example, starch,
gelatine or acacia; and lubricating agents, for example magnesium
stearate, stearic acid or talc. The tablets may be uncoated or they may
be coated by known techniques to delay disintegration and absorption in
the gastrointestinal tract and thereby provide a sustained action over a
longer period. For example, a time delay material such as glyceryl
monostearate or glyceryl distearate may be employed. They may also be
coated by the techniques described in U.S. Pat. Nos. 4,356,108;
4,166,452; and 4,265,874, incorporated herein by reference, to form
osmotic therapeutic tablets for controlled release.

[1126] Formulations for oral use may also be presented as hard gelatine
capsules where the active ingredient is mixed with an inert solid
diluent, for example, calcium carbonate, calcium phosphate or kaolin, or
a soft gelatine capsule wherein the active ingredient is mixed with water
or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

[1127] Aqueous suspensions may contain the active compounds in admixture
with excipients suitable for the manufacture of aqueous suspensions. Such
excipients are suspending agents, for example sodium
carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,
sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;
dispersing or wetting agents may be a naturally-occurring phosphatide
such as lecithin, or condensation products of an alkylene oxide with
fatty acids, for example polyoxyethylene stearate, or condensation
products of ethylene oxide with long chain aliphatic alcohols, for
example, heptadecaethyl-eneoxycetanol, or condensation products of
ethylene oxide with partial esters derived from fatty acids and a hexitol
such as polyoxyethylene sorbitol monooleate, or condensation products of
ethylene oxide with partial esters derived from fatty acids and hexitol
anhydrides, for example polyethylene sorbitan monooleate. The aqueous
suspensions may also contain one or more colouring agents, one or more
flavouring agents, and one or more sweetening agents, such as sucrose or
saccharin.

[1128] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil, sesame
oil or coconut oil, or in a mineral oil such as a liquid paraffin. The
oily suspensions may contain a thickening agent, for example beeswax,
hard paraffin or cetyl alcohol. Sweetening agents such as those set forth
above, and flavouring agents may be added to provide a palatable oral
preparation. These compositions may be preserved by the addition of an
anti-oxidant such as ascorbic acid.

[1129] Dispersible powders and granules suitable for preparation of an
aqueous suspension by the addition of water provide the active compound
in admixture with a dispersing or wetting agent, suspending agent and one
or more preservatives. Suitable dispersing or welting agents and
suspending agents are exemplified by those already mentioned above.
Additional excipients, for example, sweetening, flavouring, and colouring
agents may also be present.

[1130] The pharmaceutical compositions comprising a compound for use
according to the present invention may also be in the form of
oil-in-water emulsions. The oily phase may be a vegetable oil, for
example, olive oil or arachis oil, or a mineral oil, for example a liquid
paraffin, or a mixture thereof. Suitable emulsifying agents may be
naturally-occurring gums, for example gum acacia or gum tragacanth,
naturally-occurring phosphatides, for example soy bean, lecithin, and
esters or partial esters derived from fatty acids and hexitol anhydrides,
for example sorbitan monooleate, and condensation products of said
partial esters with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening and flavouring
agents.

[1131] Syrups and elixirs may be formulated with sweetening agents, for
example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, preservative and flavouring
and colouring agent. The pharmaceutical compositions may be in the form
of a sterile injectable aqueous or oleaginous suspension. This suspension
may be formulated according to the known methods using suitable
dispersing or wetting agents and suspending agents described above. The
sterile injectable preparation may also be a sterile injectable solution
or suspension in a non-toxic parenterally-acceptable diluent or solvent,
for example as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's solution,
and isotonic sodium chloride solution. In addition, sterile, fixed oils
are conveniently employed as solvent or suspending medium. For this
purpose, any bland fixed oil may be employed using synthetic mono- or
diglycerides. In addition, fatty acids such as oleic acid find use in the
preparation of injectables.

[1132] The compositions may also be in the form of suppositories for
rectal administration of the compounds of the present invention. These
compositions can be prepared by mixing the drug with a suitable
non-irritating excipient which is solid at ordinary temperatures but
liquid at the rectal temperature and will thus melt in the rectum to
release the drug. Such materials include cocoa butter and polyethylene
glycols, for example.

[1133] For topical use, creams, ointments, jellies, solutions of
suspensions, etc., containing the compounds of the present invention are
contemplated. For the purpose of this application, topical applications
shall include mouth washes and gargles.

[1134] The compounds for use according to the present invention may also
be administered in the form of liposome delivery systems, such as small
unilamellar vesicles, large unilamellar vesicles, and multilamellar
vesicles. Liposomes may be formed from a variety of phospholipids, such
as cholesterol, stearylamine, or phosphatidylcholines.

[1135] In addition, some of the compounds for use according to the present
invention may form solvates with water or common organic solvents. Such
solvates are also encompassed within the scope of the present invention.

[1136] Thus, in a further embodiment, there is provided a pharmaceutical
composition comprising a compound for use according to the present
invention, or a pharmaceutically acceptable salt, solvate, or prodrug
thereof, and one or more pharmaceutically acceptable carriers,
excipients, or diluents.

[1137] If a solid carrier is used for oral administration, the preparation
may be tabletted, placed in a hard gelatine capsule in powder or pellet
form or it can be in the form of a troche or lozenge. The amount of solid
carrier will vary widely but will usually be from about 25 mg to about 1
g. If a liquid carrier is used, the preparation may be in the form of a
syrup, emulsion, soft gelatine capsule or sterile injectable liquid such
as an aqueous or non-aqueous liquid suspension or solution.

[1139] The compounds of the invention may be administered to a patient
which is a mammal, especially a human in need thereof. Such mammals
include also animals, both domestic animals, e.g. household pets, and
non-domestic animals such as wildlife.

[1140] Any novel feature or combination of features described herein is
considered essential to this invention.

[1141] The present invention also relate to the below methods of preparing
the compounds of the invention.

[1142] The present invention is further illustrated in the following
representative examples which are, however, not intended to limit the
scope of the invention in any way.

EXAMPLES

Compounds of General Formulas (I) and (II)

[1143] The following examples and general procedures refer to intermediate
compounds and final products for general formula (I) and (II) identified
in the specification and in the synthesis schemes. The preparation of the
compounds of general formula (I) and (II) of the present invention is
described in detail using the following examples. Occasionally, the
reaction may not be applicable as described to each compound included
within the disclosed scope of the invention.

[1144] The compounds for which this occurs will be readily recognised by
those skilled in the art. In these cases the reactions can be
successfully performed by conventional modifications known to those
skilled in the art, which is, by appropriate protection of interfering
groups, by changing to other conventional reagents, or by routine
modification of reaction conditions. Alternatively, other reactions
disclosed herein or otherwise conventional will be applicable to the
preparation of the corresponding compounds of the invention. In all
preparative methods, all starting materials are known or may easily be
prepared from known starting materials. The structures of the compounds
are confirmed by either elemental analysis or nuclear magnetic resonance
(NMR), where peaks assigned to characteristic protons in the title
compounds are presented where appropriate. .sup.1H NMR shifts
(.delta..sub.H) are given in parts per million (ppm) down field from
tetramethylsilane as internal reference standard. M.p.: is melting point
and is given in .degree. C. and is not corrected. Column chromatography
was carried out using the technique described by W. C. Still et al., J.
Org. Chem. 43: 2923 (1978) on Merck silica gel 60 (Art. 9385). HPLC
analyses are performed using 5 .mu.m C18 4.times.250 mm column eluted
with various mixtures of water and acetonitrile, flow=1 ml/min, as
described in the experimental section.

Microwave oven synthesis: The reaction was heated by microwave
irradiation in sealed microwave vessels in a single mode Emrys Optimizer
EXP from PersonalChemistry.RTM..

[1145] Preparative HPLC: Column: 1.9.times.15 cm Waters XTerra RP-18.
Buffer: linear gradient 5-95% in 15 min, MeCN, 0.1% TFA, flow rate of 15
ml/min. The pooled fractions are either evaporated to dryness in vacuo,
or evaporated in vacuo until the MeCN is removed, and then frozen and
freeze dried.

[1146] The abbreviations as used in the examples have the following
meaning:

TLC: Thin layer chromatography

CDCl.sub.3: Deuterio chloroform

CD.sub.3OD: Tetradeuterio methanol

DCM: Dichloromethane

DMF: N,N-dimethylformamide

DMSO-d.sub.6: Hexadeuterio dimethylsulfoxide

DMSO: Dimethylsulfoxide

DIPEA: Diisopropylethylamine

EDAC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

EtOAc: Ethyl acetate

THF: Tetrahydrofuran

DMF: N,N-dimethylformamide

HOBT: 1-Hydroxy-benzotriazole

MeCN: Acetonitrile

NMP: N-Methylpyrrolidinone

TFA: Trifluoroacetic acid

EDAC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride

min: minutes

hrs: hours

[1147] General Method A:

[1148] By allowing an acid (I) wherein R.sup.3 is defined as above to be
coupled with an amine (II) wherein R.sup.1 and R.sup.2 are defined as
above under standard amide forming conditions using a coupling reagent
(III) (e.g. HOBT, EDAC and DIPEA in dry THF) affording amide (IV) wherein
R.sup.1, R.sup.2 and R.sup.3 are defined as above. General Method B:

[1149] By allowing an acid derivative (I) wherein X is halo,
R.sup.3(C.dbd.O)O--, C.sub.1-C.sub.6alkyloxy or
arylC.sub.1-C.sub.6alkyloxy and R.sup.3 are defined as above to react
with an amine (II) wherein R.sup.1 and R.sup.2 are defined as above under
basic conditions (e.g. triethylamine, K.sub.2CO.sub.3, NaH and the like)
in a solvent (e.g. THF, DCM, DMF, NMP and the like) affording amide
(III); wherein R.sup.1, R.sup.2 and R.sup.3 are defined as above.
General Method C:

[1150] By allowing an acid derivative (I) wherein X is halo,
R.sup.20(C.dbd.O)O--, C.sub.1-C.sub.6alkyloxy or
arylC.sub.1-C.sub.6alkyloxy, R.sup.20 is C.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkyl and R.sup.3 and X are defined as above to react
with an amine (II) wherein R.sup.1 and R.sup.2 are defined as above under
basic conditions (e.g. triethylamine, K.sub.2CO.sub.3, NaH and the like)
in a solvent (e.g. THF, DCM, DMF, NMP and the like) affording amide
(III); wherein R.sup.1, R.sup.2 and R.sup.3 are defined as above; or when
X is hydroxy the acid derivative (I) wherein R.sup.3 is as defined above
is coupled with an amine (II) wherein R.sup.1 and R.sup.2 are defined as
above under standard amide forming conditions using a coupling reagent
(a) (e.g. HOBT, EDAC and DIPEA in dry THF) affording amide (III) wherein
R.sup.1, R.sup.2 and R.sup.3 are as defined above.

Example 1

General Method (A)

4-(Benzo[1,3]-dioxol-5-yloxy)-N-cyclohexyl-N-methyl-butyramide

[1151]

[1152] To a solution of 4-(benzo[1,3]dioxol-5-yloxy)-butyric acid (1.0 g,
4.46 mmol), HOBT (0.66 g, 4.91 mmol) in dry THF (75 ml) was added EDAC
(0.94 g, 4.91 mmol) and the mixture was stirred for 20 minutes.
Di-isopropyl ethyl amine (DIPEA) (860 .mu.l, 4.91 mmol) and
cyclohexyl-methyl-amine (555 mg, 4.91 mmol) was added and the resulting
mixture was stirred for 16 hrs. at room temperature. The volatiles were
evaporated in vacuo and the residue was purified by silicagel
chromatography using a mixture of ethyl acetate/hexane (1:4) as eluent.
Pure fractions were collected and the solvent evaporated in vacuo to
dryness. The oily residue crystallized on standing affording 1.1 g (77%)
of the title compounds as a solid.

[1158] To a solution of 4-phenoxy-butyric acid (1.0 g, 5.55 mmol), HOBT
(0.83 g, 6.1 mmol) in dry THF (75 ml) was added EDAC (1.17 g, 6.1 mmol)
and the mixture was stirred for 20 minutes. Di-isopropyl ethyl amine
(DIPEA) (1.06 ml, 6.1 mmol) and methyl-(1-methyl-piperidin-4-yl)amine
(783 mg, 6.1 mmol) was added and the resulting mixture was stirred for 16
hrs. at room temperature. The volatiles were evaporated in vacuo and the
residue was purified by silicagel chromatography using a mixture of ethyl
acetate/triethyl amine (1:25) as eluent. Pure fractions were collected
and the solvent evaporated in vacuo to dryness affording 1.1 g (68%) of
the title compounds as an oil.

[1164] To a solution of 3-chloro benzoic acid (1.0 g, 6.39 mmol), HOBT
(0.95 g, 7.03 mmol) in dry THF (50 ml) was added EDAC (1.35 g, 7.03 mmol)
and the mixture was stirred for 20 minutes. Di-isopropyl ethyl amine
(DIPEA) (1.22 ml, 7.03 mmol) and azepane (697 mg, 7.03 mmol) was added
and the resulting mixture was stirred for 4 hrs. at room temperature. The
volatiles were evaporated in vacuo, water (50 ml) was added, the
resulting mixture extracted with diethyl ether (2.times.25 ml), dried
(Na.sub.2SO.sub.4), filtered and evaporated in vacuo. The residue was
purified by silicagel chromatography using a mixture of ethyl
acetate/heptane (1:1) as eluent. Pure fractions were collected and the
solvent evaporated in vacuo to dryness affording 0.9 g (59%) of the title
compounds as an oil.

[1167] To a mixture of 4-(1H-tetrazol-5-yl)-benzoic acid (0.5 g, 2.63
mmol) and HOBT (0.39 g, 2.89 mmol) in dry THF (35 mL) was added EDAC
(0.55 g, 2.89 mmol). The resulting mixture was stirred for 10 min.
followed by addition of a mixture of DIPEA (0.50 ml, 2.89 mmol) and
1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane (0.49 ml, 2.89 mmol). The
reaction mixture was stirred for an additional 6 hrs. and evaporated to
dryness. To the residue was added water (10 ml) and the resulting mixture
was extracted with diethyl ether (2.times.10 ml). The combined organic
phases were dried (Na.sub.2SO.sub.4), filtered and evaporated in vacuo.
The resulting residue was purified by column chromatography (silica gel)
using a mixture of EtOAc-Heptane (1:2) as eluent. Pure fractions were
collected and evaporated to dryness. To the residue was added diethyl
ether (5 ml) and the precipitate was filtered off, washed with diethyl
ether and dried in vacuo at 50.degree. C. affording 220 mg (26%) of the
title compound as a solid.

[1172] To a mixture of 8-aza-bicyclo[3.2.1]octane (1.8 g, 14.38 mmol), dry
THF (75 ml) and TEA (4 ml, 28.76 mmol) was added dropwise a solution of
4-dimethylamino-benzoyl chloride (3.17 g, 17.26 mmol) in dry THF (75 ml).
The resulting mixture was stirred for 1 hr. at room temperature followed
by filtration and evaporation in vacuo. The residue was purified by
column chromatography (silica gel) using a mixture of EtOAc-Heptane (1:2)
as eluent. Pure fractions were collected and evaporated to dryness. The
residue was crystallized from diethyl ether (25 ml), filtered off and
dried in vacuo at 50.degree. C. affording 1.9 g (48%) of the title
compound as a solid.

[1176] To a solution of
8-(4-dimethylamino-benzoyl)-8-aza-bicyclo[3.2.1]octan-3-one (2.0 g, 7.34
mmol) in MeOH (75 ml) was added NaBH.sub.4 (0.45 g, 11.02 mmol, pellets).
The resulting mixture was stirred for 18 hrs, evaporated and to the
residue was added water (75 ml). The aqueous phase was acidified to pH 1
with conc. HCl and washed with diethyl ether (50 ml). The aqueous phase
was neutralized to pH 7 with 1N NaOH. The precipitate was filtered off
and washed with water, diethyl ether and dried in vacuo at 50.degree. C.
affording 1.15 g (57%) of the title compound as a solid.

[1179] To a solution of
8-(4-dimethylamino-benzoyl)-8-aza-bicyclo[3.2.1]octan-3-one (200 mg,
0.734 mmol) in dry THF (40 ml) was added dropwise a solution of
methylmagnesium bromide (0.74 ml, 2.20 mmol, 3M in diethyl ether). The
resulting mixture was stirred for 36 hrs. at room temperature and
quenched by addition of saturated aqueous ammonium chloride (50 ml). The
aqueous phase was extracted with EtOAc (2.times.100 ml) and the combined
organic phases were dried (Na.sub.2SO.sub.4), filtered and evaporated in
vacuo. The residue was purified by column chromatography (silica gel)
using a mixture of EtOAc-Heptane (5:1) as eluent. Pure fractions were
collected and evaporated to dryness affording 45 mg (21%) of the title
compound as a solid. TLC: EtOAc, R.sub.f: 0.39

[1182] NaBH.sub.4 (0.3 g, 2 pellets) was added to TFA (20 ml) at 0.degree.
C. and stirred for 30 min. To this mixture was added a solution of
8-(4-dimethylamino-benzoyl)-8-aza-bicyclo[3.2.1]octan-3-one (0.3 g, 1.102
mmol) in DCM (10 ml). The resulting mixture was stirred for 64 hrs. at
room temperature, the volatiles evaporated and to the residue was added
water (10 ml). The aqueous phase was neutralized to pH 7 with 1N NaOH and
extracted with diethyl ether (2.times.25 ml). The combined organic phases
were evaporated in vacuo and the residue purified by column
chromatography (silica gel) using a mixture of EtOAc-Heptane (1:2) as
eluent. Pure fractions were collected and evaporated to dryness affording
25 mg (9%) of the title compound as a solid. TLC: EtOAc-Heptane (2:1),
R.sub.f: 0.54

[1185] The following examples and general procedures refer to intermediate
compounds and final products for general formula (III) identified in the
specification and in the synthesis schemes. The preparation of the
compounds of general formula (III) of the present invention is described
in detail using the following examples. Occasionally, the reaction may
not be applicable as described to each compound included within the
disclosed scope of the invention. The compounds for which this occurs
will be readily recognised by those skilled in the art. In these cases
the reactions can be successfully performed by conventional modifications
known to those skilled in the art, that is, by appropriate protection of
interfering groups, by changing to other conventional reagents, or by
routine modification of reaction conditions. Alternatively, other
reactions disclosed herein or otherwise conventional will be applicable
to the preparation of the corresponding compounds of the invention. In
all preparative methods, all starting materials are known or may easily
be prepared from known starting materials. The structures of the
compounds are confirmed by either elemental analysis or nuclear magnetic
resonance (NMR), where peaks assigned to characteristic protons in the
title compounds are presented where appropriate. .sup.1H NMR shifts (8H)
are given in parts per million (ppm) down field from tetramethylsilane as
internal reference standard. M.p.: is melting point and is given in
.degree. C. and is not corrected. Column chromatography was carried out
using the technique described by W. C. Still et al., J. Org. Chem. 43:
2923 (1978) on Merck silica gel 60 (Art. 9385). HPLC analyses are
performed using 5 .mu.m C18 4.times.250 mm column eluted with various
mixtures of water and acetonitrile, flow=1 ml/min, as described in the
experimental section.

[1186] The abbreviations as used in the examples have the following
meaning:

TLC: thin layer chromatography

CDCl.sub.3: deuterio chloroform

CD.sub.3OD: tetradeuterio methanol

DMSO-d.sub.6: hexadeuterio dimethylsulfoxide

DMSO: dimethylsulfoxide

THF: tetrahydrofuran

DMF: N,N-dimethylformamide

HOBT: 1-hydroxy-benzotriazole

EDAC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride

min: minutes

hrs: hours

[1187] The compounds of the invention are prepared as illustrated in the
following reaction scheme 1: General Method:

[1188] By allowing 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) (I)
to react with an acid chloride (II), wherein R.sup.2 is defined above, in
a solvent mixture of pyridine and DCM and the like affording an acyl
Meldrum's acid (III), wherein R.sup.2 is as defined above. The acyl
Meldrum's acid (III) is aminolysed with an substituted amine (IV),
wherein R.sup.3 and R.sup.4 are defined above, in a solvent such as
benzene, toluene, dioxane, and the like at a temperature interval from
50.degree. C. up to reflux affording a beta-keto amide (V) wherein
R.sup.2, R.sup.3 and R.sup.4 are as defined above. The beta-keto amide
(V) is treated with ortho-formiate (VI) in a solvent such as acetic acid
anhydride and the like at a temperature interval from 50.degree. C. up to
reflux affording enol ether (VII) wherein R.sup.2, R.sup.3, and R.sup.4
are as defined above. Condensation of the enol ether (VII) wherein
R.sup.2, R.sup.3, and R.sup.4 are as defined above with hydrazide (VIII)
wherein R.sup.1 is as defined above yields pyrazole (IX) wherein R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 are as defined above, in a solvent such as
EtOH, i-PrOH, tert-BuOH and the like.

[1190] To a solution of
1-(4-chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic acid (1.0 g, 3.78
mmol), HOBT (0.56 g, 4.16 mmol) in dry THF (50 ml) was added EDAC (0.8 g,
4.16 mmol) and the mixture was stirred for 10 minutes. Di-isopropyl ethyl
amine (DIPEA) (724 .mu.l, 4.16 mmol) and cyclohexyl-methyl-amine (0.54
ml, 4.16 mmol) was added and the resulting mixture was stirred for 16
hrs. at room temperature. The volatiles were evaporated in vacuo and the
residue was purified by silicagel chromatography using a mixture of ethyl
acetate and heptane (1:4) as eluent. Pure fractions were collected and
the solvent evaporated in vacuo affording 1.1 g (81%) of the title
compounds as an oil.

[1200] The following examples and general procedures refer to intermediate
compounds and final products for general formula (IV) identified in the
specification and in the synthesis schemes. The preparation of the
compounds of general formula (IV) of the present invention is described
in detail using the following examples. Occasionally, the reaction may
not be applicable as described to each compound included within the
disclosed scope of the invention. The compounds for which this occurs
will be readily recognised by those skilled in the art. In these cases
the reactions can be successfully performed by conventional modifications
known to those skilled in the art, that is, by appropriate protection of
interfering groups, by changing to other conventional reagents, or by
routine modification of reaction conditions. Alternatively, other
reactions disclosed herein or otherwise conventional will be applicable
to the preparation of the corresponding compounds of the invention. In
all preparative methods, all starting materials are known or may easily
be prepared from known starting materials. The structures of the
compounds are confirmed by either elemental analysis or nuclear magnetic
resonance (NMR), where peaks assigned to characteristic protons in the
title compounds are presented where appropriate. .sup.1H NMR shifts (6H)
are given in parts per million (ppm) down field from tetramethylsilane as
internal reference standard. M.p.: is melting point and is given in
.degree. C. and is not corrected. Column chromatography was carried out
using the technique described by W. C. Still et al., J. Org. Chem. 43:
2923 (1978) on Merck silica gel 60 (Art. 9385). HPLC analyses are
performed using 5 .mu.m C18 4.times.250 mm column eluted with various
mixtures of water and acetonitrile, flow=1 ml/min, as described in the
experimental section.

[1201] The abbreviations as used in the examples have the following
meaning:

TLC: Thin layer chromatography

CDCl.sub.3: Deuterio chloroform

CD.sub.3OD: Tetradeuterio methanol

DMSO-d.sub.6: Hexadeuterio dimethylsulfoxide

DMSO: Dimethylsulfoxide

THF: Tetrahydrofuran

DMF: N,N-Dimethylformamide

HOBT: 1-Hydroxy-benzotriazole

EDAC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride

min: minutes

hrs: hours

[1202] The compounds of the invention are prepared as illustrated in the
following reaction scheme 1: General Method:

[1203] By allowing a N-aminopyridinium iodide (I), wherein R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are as defined, above to react with a
propiolate (II), wherein alkyl and R.sup.1 are as defined above, in a
solvent such as DMF and the like, with a suitable base, such as potassium
carbonate and the like affording a pyrazolo[1,5-a]pyridine-3-carboxylic
acid ester (III), wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and
alkyl are as defined above. The pyrazolo[1,5-a]pyridine-3-carboxylic acid
ester (III) is hydrolysed with a base affording a
pyrazolo[1,5-a]pyridine-3-carboxylic acid (IV), wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are as defined above. The
pyrazolo[1,5-a]pyridine-3-carboxylic acid (IV) is coupled with an amine
(V), wherein R.sup.6 and R.sup.7 are as defined above, under standard
amide forming conditions (e.g. HOBT, EDAC and DIPEA in dry THF) affording
pyrazolo[1,5-a]pyridine-3-amide (VI), wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are as defined above.

[1212] The following examples and general procedures refer to intermediate
compounds and final products for general formulas (V) and (Va) identified
in the specification and in the synthesis schemes. The preparation of the
compounds of general formulas (V) and (Va) of the present invention is
described in detail using the following examples. Occasionally, the
reaction may not be applicable as described to each compound included
within the disclosed scope of the invention. The compounds for which this
occurs will be readily recognised by those skilled in the art. In these
cases the reactions can be successfully performed by conventional
modifications known to those skilled in the art, that is, by appropriate
protection of interfering groups, by changing to other conventional
reagents, or by routine modification of reaction conditions.
Alternatively, other reactions disclosed herein or otherwise conventional
will be applicable to the preparation of the corresponding compounds of
the invention. In all preparative methods, all starting materials are
known or may easily be prepared from known starting materials. The
structures of the compounds are confirmed by either elemental analysis or
nuclear magnetic resonance (NMR), where peaks assigned to characteristic
protons in the title compounds are presented where appropriate. .sup.1H
NMR shifts (.delta..sub.H) are given in parts per million (ppm) down
field from tetramethylsilane as internal reference standard. M.p.: is
melting point and is given in .degree. C. and is not corrected. Column
chromatography was carried out using the technique described by W. C.
Still et al., J. Org. Chem. 43: 2923 (1978) on Merck silica gel 60 (Art.
9385). HPLC analyses are performed using 5 .mu.m C18 4.times.250 mm
column eluted with various mixtures of water and acetonitrile, flow=1
ml/min, as described in the experimental section.

[1213] The abbreviations as used in the examples have the following
meaning:

TLC: Thin layer chromatography

CDCl.sub.3: Deuterio chloroform

CD.sub.3OD: Tetradeuterio methanol

DIPEA: Diisopropylethyl amine

DMSO-d.sub.6: Hexadeuterio dimethylsulfoxide

DMSO: Dimethylsulfoxide

THF: Tetrahydrofuran

DMF: N,N-dimethylformamide

HOBT: 1-Hydroxy-benzotriazole

EDAC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride

min: minutes

hrs: hours

[1214] The compounds of the invention are prepared as illustrated in the
following reaction schemes: General Method A

[1222] By allowing an acid derivative (I) wherein X is halo,
R.sup.8(C.dbd.O)O--, C.sub.1-C.sub.6alkyloxy or
arylC.sub.1-C.sub.6alkyloxy, R.sup.8 is C.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkyl and R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6
and R.sup.7 are defined as above to react with an amine (II) wherein
R.sup.6 and R.sup.7 are defined as above under basic conditions (e.g.
triethylamine, K.sub.2CO.sub.3, NaH and the like) in a solvent (e.g. THF,
DCM, DMF, NMP and the like) affording amide (III); wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are defined as
above. General Method A

[1229] By allowing an acid (I) wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5,
and R.sup.6 are as defined above to be coupled with an amine (II) wherein
R.sup.7 and R.sup.8 are defined as above under standard amide forming
conditions using a coupling reagent (a) (e.g. HOBT, EDAC and DIPEA in dry
THF) affording amide (III) wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5,
R.sup.5, R.sup.7 and R.sup.8 are as defined above. General Method B

[1230] By allowing an acid derivative (I) wherein X is halo,
R.sup.9(C.dbd.O)O--, C.sub.1-C.sub.6alkyloxy or
arylC.sub.1-C.sub.6alkyloxy, R.sup.9 is C.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkyl and R.sup.1, R.sup.2, R.sup.3, R.sup.5 and
R.sup.6 are defined as above to react with an amine (II) wherein R.sup.7
and R.sup.8 are defined as above under basic conditions (e.g.
triethylamine, K.sub.2CO.sub.3, NaH and the like) in a solvent (e.g. THF,
DCM, DMF, NMP and the like) affording amide (III); wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are
defined as above.

Example 1

1H-Benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide

[1231]

[1232] A solution of 1H-benzoimidazole-5-carboxylic acid (10 g, 61.67
mmol) and HOBT (9.17 g, 67.84 mmol) in dry THF (250 ml) was stirred for 1
h. EDAC (13 g, 67.84 mmol) was added and the mixture was stirred for
another 1 h. Di-isopropyl ethyl amine (DIPEA) (11.8 ml, 67.84 mmol) and
cyclohexyl-methyl-amine (8.8 ml, 67.84 mmol) was added and the resulting
mixture was stirred for 16 hrs. at room temperature. The precipitate was
filtered off and the volatiles were evaporated in vacuo. To the residue
was added water (150 ml) and diethyl ether (75 ml) and the resulting
mixture was stirred for 15 minutes. The precipitate was filtered off and
washed with water followed by diethyl ether and drying in vacuo at
50.degree. C. which afforded 7.7 g (49%) of the title compounds as a
solid.

[1265] The following examples and general procedures refer to intermediate
compounds and final products for general formula (VI) identified in the
specification and in the synthesis schemes. The preparation of the
compounds of general formula (VI) of the present invention is described
in detail using the following examples. Occasionally, the reaction may
not be applicable as described to each compound included within the
disclosed scope of the invention. The compounds for which this occurs
will be readily recognised by those skilled in the art. In these cases
the reactions can be successfully performed by conventional modifications
known to those skilled in the art, that is, by appropriate protection of
interfering groups, by changing to other conventional reagents, or by
routine modification of reaction conditions. Alternatively, other
reactions disclosed herein or otherwise conventional will be applicable
to the preparation of the corresponding compounds of the invention. In
all preparative methods, all starting materials are known or may easily
be prepared from known starting materials. The structures of the
compounds are confirmed by either elemental analysis or nuclear magnetic
resonance (NMR), where peaks assigned to characteristic protons in the
title compounds are presented where appropriate. .sup.1H NMR shifts (8H)
are given in parts per million (ppm) down field from tetramethylsilane as
internal reference standard. M.p.: is melting point and is given in
.degree. C. and is not corrected. Column chromatography was carried out
using the technique described by W. C. Still et al., J. Org. Chem. 43:
2923 (1978) on Merck silica gel 60 (Art. 9385). HPLC analyses are
performed using 5 .mu.m C18 4.times.250 mm column eluted with various
mixtures of water and acetonitrile, flow=1 ml/min, as described in the
experimental section.

[1266] The abbreviations as used in the examples have the following
meaning:

TLC: thin layer chromatography

CDCl.sub.3: deuterio chloroform

CD.sub.3OD: tetradeuterio methanol

DMSO-d.sub.6: hexadeuterio dimethylsulfoxide

DMSO: dimethylsulfoxide

THF: tetrahydrofuran

DMF: N,N-dimethylformamide

HOBT: 1-hydroxy-benzotriazole

EDAC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride

min: minutes

hrs: hours

[1267] The compounds of the invention are prepared as illustrated in the
following reaction scheme 1: General Method A:

[1269] By allowing an acid derivative (I) wherein Y is halo,
R.sup.13(C.dbd.O)O--, C.sub.1-C.sub.6alkyloxy or
arylC.sub.1-C.sub.6alkyloxy, R.sup.13 is C.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkyl and R.sup.3, R.sup.4, R.sup.7 and X are defined
as above to react with an amine (II) wherein R.sup.5 and R.sup.6 are
defined as above under basic conditions (e.g. triethylamine,
K.sub.2CO.sub.3, NaH and the like) in a solvent (e.g. THF, DCM, DMF, NMP
and the like) affording amide (III); wherein R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7 and X are defined as above.

[1280] To a solution of 2,3-dimethyl-2,3-dihydro-benzofuran-7-carboxylic
acid (0.5 g, 2.60 mmol), HOBT (0.39 g, 2.86 mmol) in dry THF (25 ml) was
added EDAC (0.55 g, 2.86 mmol). The mixture was stirred for 10 min.
followed by addition of di-isopropyl ethyl amine (DIPEA) (0.5 ml, 2.86
mmol) and cyclohexyl-methyl-amine (0.37 ml, 2.86 mmol). The resulting
mixture was stirred for 16 hrs. at room temperature, the volatiles were
evaporated in vacuo and to the residue was added water (25 ml) and
diethyl ether (75 ml). The organic phase was separated and dried
(Na.sub.2SO.sub.4), filtered and the solvent evaporated in vacuo. The
residue was dissolved in a mixture of AcOEt/Heptane (1:1) and filtered
through a 2.5 cm silicagel plug. The solvent was evaporated in vacuo
affording 0.7 g (93%) of the title compounds as an oil.

[1286] The following examples and general procedures refer to intermediate
compounds and final products for general formula (VII) identified in the
specification and in the synthesis schemes. The preparation of the
compounds of general formula (VII) of the present invention is described
in detail using the following examples. Occasionally, the reaction may
not be applicable as described to each compound included within the
disclosed scope of the invention. The compounds for which this occurs
will be readily recognised by those skilled in the art. In these cases
the reactions can be successfully performed by conventional modifications
known to those skilled in the art, that is, by appropriate protection of
interfering groups, by changing to other conventional reagents, or by
routine modification of reaction conditions. Alternatively, other
reactions disclosed herein or otherwise conventional will be applicable
to the preparation of the corresponding compounds of the invention. In
all preparative methods, all starting materials are known or may easily
be prepared from known starting materials. The structures of the
compounds are confirmed by nuclear magnetic resonance (NMR), where peaks
assigned to characteristic protons in the title compounds are presented
where appropriate. .sup.1H NMR shifts (.delta...sub.H) are given in parts
per million (ppm) down field from tetramethylsilane as internal reference
standard. M.p.: is melting point and is given in .degree. C. and is not
corrected. Column chromatography was carried out using the technique
described by W. C. Still et al., J. Org. Chem. 43: 2923 (1978) on Merck
silica gel 60 (Art. 9385). LC-MS analyses are performed using Waters
XTerra MS C-3.times.18 mm RP-C18 column eluted with various mixtures of
water and acetonitrile, flow=1 mL/min, with UV detection at 210 nm and MS
scanning (ES+) from 100-1000 amu. An injection volume of 1 .mu.L was
used.

Microwave oven synthesis: The reaction was heated by microwave
irradiation in sealed microwave vessels in a single mode Emrys Optimizer
EXP from PersonalChemistry.RTM..

Solid-phase synthesis: All reactions were performed in Teflon apparatus
suitable for solid-phase synthesis or on an ACT 496 robot employing the
standard procedures described.

[1287] Preparative HPLC: Column: 1.9.times.15 cm Waters XTerra RP-18.
Buffer: linear gradient 5-95% in 15 min, MeCN, 0.1% TFA, flow rate of 15
mL/min. The pooled fractions are either evaporated to dryness in vacuo,
or evaporated in vacuo until the MeCN is removed, and then frozen and
freeze dried.

The abbreviations as used in the examples have the following meaning:

TLC: Thin layer chromatography

CDCl.sub.3: Deuterio chloroform

CD.sub.3OD: Tetradeuterio methanol

DMSO-d.sub.6: Hexadeuterio dimethylsulfoxide

DMSO: Dimethylsulfoxide

THF: Tetrahydrofuran

DMF: N,N-dimethylformamide

HOBT: 1-Hydroxy-benzotriazole

EDAC: 1-(3-Ddimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride

min: minutes

hrs: hours

[1288] The compounds of the invention are prepared as illustrated in the
following reaction schemes: General Method A

[1339] A solution of 1H-indole-5-carboxylic acid (1.0 g, 6.21 mmol), HOBT
(0.9 g, 6.83 mmol) in dry THF (50 mL) and EDAC (1.31 g, 6.83 mmol) was
stirred for 10 mins. Di-isopropyl ethyl amine (DIPEA) (1.2 mL, 6.83 mmol)
and 6-aza-bicyclo[3.2.1]octyl)-amine (1.16 mL, 6.83 mmol) was added and
the resulting mixture was stirred for 16 hrs. at room temperature. The
volatiles were evaporated in vacuo and to the residue was added water (25
mL) followed by extraction with diethyl ether (2.times.25 mL). The
combined organic phases were dried (Na.sub.2SO.sub.4), filtered and
evaporated in vacuo. The residue was purified by silicagel chromatography
using a mixture of ethyl acetate and heptane (1:2) as eluent. Pure
fractions were collected and the solvent evaporated in vacuo. To the
residue was added diethyl ether (10 mL) and the resulting mixture was
stirred for 1 h. The precipitate was filtered off and dried in vacuo at
50.degree. C. affording 1.3 g (71%) of the title compounds as a solid.

[1347] A solution of 1H-indole-7-carboxylic acid (323 mg, 2 mmol), HOAt
(300 mg, 2.2 mmol) in dry DMF (10 mL) and EDAC (500 mg, 2.6 mmol) was
stirred for 10 mins. Triethylamine (TEA) (0.84 mL, 6 mmol) and
6-aza-bicyclo[3.2.1]octyl)-amine (338 mg, 2.2 mmol) was added and the
resulting mixture was stirred for 16 hrs. at room temperature. The
volatiles were evaporated in vacuo and to the residue was added water (10
mL) followed by extraction with dichloromethane (DCM, 2.times.25 mL). The
combined organic phases were dried (MgSO.sub.4), filtered and evaporated
in vacuo. The residue was purified by preparative HPLC, dried in vacuo at
50.degree. C. affording 283 mg (47%) of the title compound as a solid.

[1350] A solution of 1H-indole-6-carboxylic acid (1 g, 6.2 mmol), HOAt
(929 mg, 6.82 mmol) in dry DMF (20 mL) and EDAC (1.54 g, 8.06 mmol) was
stirred for 10 mins. TEA (2.59 mL, 18.6 mmol) and
6-aza-bicyclo[3.2.1]octyl)-amine (1.04 g, 6.82 mmol) was added and the
resulting mixture was stirred for 5 hrs. at room temperature. The
volatiles were evaporated in vacuo and to the residue was added water (10
mL) followed by extraction with dichloromethane (DCM, 2.times.50 mL). The
combined organic phases were dried (MgSO.sub.4), filtered and evaporated
in vacuo. The residue was purified by silicagel chromatography using a
mixture of ethyl acetate and heptane (3:7) as eluent. Pure fractions were
collected, the solvent evaporated in vacuo and dried in vacuo at
50.degree. C. affording 1.6 g (87%) of the title compounds as a solid.

[1354] To a solution of
(1H-Indol-6-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
(1.49 g, 5.02 mmol) in pyridine (0.81 mL, 5.02 mmol) and DCM (25 mL) at
0.degree. C. was added trichloroacetyl chloride after which cooling was
stopped and the resulting mixture was stirred for 16 hrs. at room
temperature. The volatiles were evaporated in vacuo and to the residue
was added water (20 mL) followed by extraction with dichloromethane (DCM,
2.times.50 mL). The combined organic phases were dried (MgSO.sub.4),
filtered and evaporated in vacuo to afford 2.48 g (100%) of
2,2,2-Trichloro-1-[6-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbon-
yl)-1H-indol-3-yl]-ethanone. To
2,2,2-Trichloro-1-[6-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbon-
yl)-1H-indol-3-yl]-ethanone (100 mg, 0.22 mmol) was added a solution of
ethanol:THF:1M NaOH solution (20 mL, 1:2:1, v/v/v) and the mixture was
stirred at room temperature for 5 hrs. The organic solvents were
evapourated in vacuo and the aqueous collections were acidified to pH 1
with concentrated hydrochloric acid followed by extraction with ethyl
acetate (2.times.20 mL). The combined organic phases were dried
(MgSO.sub.4), filtered, evapourated and the residue after trituration
with diethyl ether was filtered and dried in vacuo at 50.degree. C.
affording 56 mg (72%) of the title compound as a solid.

[1357] To a solution of
2,2,2-Trichloro-1-[6-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbon-
yl)-1H-indol-3-yl]-ethanone (100 mg, 0.22 mmol) in ethanol (2 mL) was
added sodium ethoxide (77 mg, 1.13 mmol) and the resulting mixture was
stirred for 16 hrs. at room temperature. The volatiles were evaporated in
vacuo and the residue was purified by preparative HPLC, dried in vacuo at
50.degree. C. affording 33 mg (43%) of the title compound as a solid.

[1361] To 4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl polystyrene (PS-TFP
resin, 100 mg, 1 mmol/g, 100-200 mesh, polystyrene-divinylbenzene 1%,
Argonaut technologies, USA) pre-swollen in DCM was added a solution of
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid (51 mg, 0.15 mmol) in DMF (0.25 mL) followed by a solution of
DMAP (7.3 mg, 0.06 mmol) in DCM (0.75 mL). The mixture was shaken for 10
min before a solution of N,N'-diisopropylcarbodiimide (DIC, 56 mg, 0.44
mmol) in DCM (0.25 mL) was added and the resulting mixture shaken for 16
hrs. at room temperature. The excess solvents were removed by filtration
and the resin was washed with DMF (3.times.1 mL) and DCM (10.times.1 mL).
To the resin was added a solution of piperidine (7.3 mg, 0.085 mmol) in
1,2-dichloroethane (1.2 mL) and DIPEA (0.03 mL, 0.17 mmol). The resulting
mixture was shaken for 16 hrs. at room temperature. The product was
removed by filtration and the resin washed with DCM:MeOH (1 mL, 3:1,
v/v). The volatiles were evaporated in vacuo and the residue was purified
by preparative HPLC, dried in vacuo at 50.degree. C. affording 22 mg
(54%) of the title compound as a solid.

[1368] To a solution of
(1H-Indol-6-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
(200 mg, 0.67 mmol) in DCM (10 mL) was added N,N-dimethylammonium iodide
and the resulting mixture stirred at room temperature for 16 hrs. The
volatiles were evaporated in vacuo and the resulting residue was purified
by preparative HPLC, dried in vacuo at 50.degree. C. affording 54 mg
(23%) of the title compound isolated as the trifluoroacetate salt.

[1371] To a solution of imidazole (23 mg, 0.34 mmol) in acetic anhydride
at 125.degree. C. was added dropwise over 40 min a solution of
(1H-Indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
(100 mg, 0.34 mmol) in acetic anhydride (13 mL). The resulting mixture
was heated at 125.degree. C. for 30 min then cooled and solvents
evaporated in vacuo. The resulting residue was purified by preparative
HPLC, dried in vacuo at 50.degree. C. to afford 5.4 mg (4%) of the title
compound as a solid.

[1374] A solution of
(1H-Indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
(100 mg, 0.34 mmol) and N-ethylmaleimide (127 mg, 1.01 mmol) in acetic
acid (2 mL) was heated at 160.degree. C. employing microwave irradiation
for 1 hr. The solvents were evaporated in vacuo and the resulting residue
purified by preparative HPLC, dried in vacuo at 50.degree. C. to afford
25 mg (18%) of the title compound as a solid.

[1377] To a slurry of
(1H-Indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
(300 mg, 1.01 mmol) in benzene (8 mL) under an inert atmosphere of
nitrogen was added methylmagnesium iodide (0.34 mL, 1.01 mmol), after
stirring for 10 mins 2-bromothiazole was added where upon the mixture was
heated at 90.degree. C. for 16 hrs. Water (20 mL) was added and the
organics were extracted with DCM (3.times.20 mL). The combined organic
phases were dried (MgSO.sub.4), filtered and evaporated in vacuo. The
residue was purified by preparative HPLC, dried in vacuo at 50.degree. C.
affording 48 mg (25%) of the title compound as a solid.

[1380] To a solution of
(1H-Indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
(1 g, 3.37 mmol) and potassium hydroxide (364 mg, 6.75 mmol) in DMF (40
mL) was added iodine (0.86 g, 3.41 mmol). The reaction mixture was
stirred for 1 hr at room temperature then poured onto water (100 mL),
extracted with DCM (3.times.20 mL). The combined organic phases were
washed with water and brine then dried (MgSO.sub.4), filtered and
evaporated in vacuo. The resulting solid was dried in vacuo at 50.degree.
C. affording 1.18 g (83%) of the title compound.

[1383] To an ice-cooled slurry of
(1H-Indol-6-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
(1 g, 3.37 mmol) in acetonitrile (25 mL) was added dropwise a solution of
chlorosulfunylisocyanate (0.48 g, 3.37 mmol). The reaction mixture was
stirred for 1 hr at 0.degree. C. then triethylamine (0.33 g, 3.3 mmol)
was added dropwise maintaining an internal temperature of 0.degree. C.
The reaction mixture was allowed to warm to room temperature over 2 hrs.
The solvents were evaporated in vacuo and the residue treated with DCM
(10 mL) and an ice cold solution of sodium bicarbonate (5%, 10 mL) and
the organics were extracted with DCM (3.times.20 mL). The combined
organic phases were dried (MgSO.sub.4), filtered and evaporated in vacuo.
The residue was purified by preparative HPLC, dried in vacuo at
50.degree. C. affording 182 mg (17%) of the title compound as a solid.

[1385] The following compound was synthesised employing a similar method
to the one described in example 14.
TABLE-US-00007
MS-ESI
No Molecule MW IUPAC Name m/z
14-1 321.42 5-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-1H-indole-3- carbonitrile 322

[1387] To a solution of
6-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
bonitrile (65 mg, 0.2 mmol) in 1,4-dioxane (2 mL) was added sodium
hydroxide solution (2 mL, 1M) and hydrogen peroxide (2 mL) and the
resulting solution was heated at 50.degree. C. for 16 hrs. The solvents
were evaporated in vacuo and the residue was purified by preparative
HPLC, dried in vacuo at 50.degree. C. affording 15 mg (21%) of the title
compound as a solid.

[1390] A slurry of
6-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
bonitrile (100 mg, 0.31 mmol), zinc bromide (70 mg, 0.31 mmol) and sodium
azide (22 mg, 0.34 mmol) in water (0.65 mL) was heated at 200.degree. C.
employing microwave irradiation for 6 min. A solution of sodium hydroxide
(3 mL, 0.25 M) was added and the mixture stirred for 45 min. Filtration
of the inorganics followed by acidification of the filtrate with
concentrated HCl to pH 1 yielded after filtration crude product which was
purified by preparative HPLC, dried in vacuo at 50.degree. C. affording 6
mg (5%) of the title compound as a solid.

[1393] To a solution of
(7-nitro-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-me-
thanone (730 mg, 2.14 mmol) in MeOH (40 mL) was added palladium on
activated charcoal (10% Pd, 50% H.sub.2O, 0.2 g). The reaction mixture
was stirred for 16 hrs under an atmosphere of hydrogen. The catalyst was
removed by filtration and the solvents were evaporated in vacuo and the
solid dried in vacuo at 50.degree. C. affording 481 mg (72%) of
(7-amino-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-me-
thanone. To a solution of
(7-amino-1H-indol-3-yl)(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-met-
hanone (100 mg, 0.32 mmol) in DCM (1 mL) was added DIPEA (829 mg, 6.4
mmol) and acetic anhydride (327 mg, 3.21 mmol), the solution was stirred
at room temperature for 1 hr. Solvents were evaporated in vacuo and the
residue was purified by preparative HPLC, dried in vacuo at 50.degree. C.
affording 47 mg (42%) of the title compound as a solid.

[1396] To a solution of
(1H-Indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
(1 g, 3.37 mmol) in dry THF (2 mL) at -78.degree. C. under an inert
atmosphere of nitrogen was added a solution of n-butyl lithium (2.14 mL,
1.65 M in hexane). Cooling was removed and the solution was allowed to
warm to room temperature with stirring. The solution was cooled to
-78.degree. C. where upon benzenesulphonyl chloride (655 mg, 3.71 mmol)
was added and the reaction mixture was stirred for 16 hrs whilst warming
to room temperature. The reaction was quenched by the addition of sodium
bicarbonate solution (5%, 200 mL) and extracted with DCM (3.times.50 mL).
The combined organic phases were washed with water and brine then dried
(MgSO.sub.4), filtered and evaporated in vacuo. The resulting solid was
purified by flash column chromatography (mobile phase ethylacetate:
heptane, 1:2). Product fractions were combined, evaporated in vacuo,
dried in vacuo at 50.degree. C. to afford 1.46 g (99%) of the title
compound.

[1399] To a solution of
(1-Benzenesulfonyl-1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1]o-
ct-6-yl)-methanone (100 mg, 0.23 mmol) in dry THF (2 mL) at -78.degree. C.
under an inert atmosphere of nitrogen was added a solution of lithium
N,N-diisopropylamide (0.165 mL, 1.5 M in cyclohexane). The mixture was
stirred for 1 hr at -78.degree. C. then cooling was removed and the
solution was allowed to warm to room temperature with stirring. The
solution was cooled to -78.degree. C. where upon methyl iodide (48 mg,
0.343 mmol) was added and the reaction mixture was stirred for 16 hrs
whilst warming to room temperature. The reaction was quenched by the
addition of saturated ammonium chloride solution (10 mL) and extracted
with DCM (3.times.10 mL). The combined organic phases were dried
(MgSO.sub.4), filtered and evaporated in vacuo. The residue was purified
by preparative HPLC, dried in vacuo at 50.degree. C. affording 12 mg
(11%) of the title compound as a solid.

[1402] To a solution of
(1H-Indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
(500 mg, 1.69 mmol) in dry DMF (10 mL) at room temperature under an inert
atmosphere of nitrogen was added sodium hydride (53 mg, 2.19 mmol, 60%
dispersion in oil), after stirring for 30 min methyl iodide (263 mg, 1.85
mmol) was added and the reaction mixture was stirred for 16 hrs at
60.degree. C. The reaction was quenched by the addition of water (20 mL)
followed by extraction with DCM (3.times.50 mL). The combined organic
phases were dried (MgSO.sub.4), filtered and evaporated in vacuo. The
resulting solid was purified by preparative HPLC, dried in vacuo at
50.degree. C. affording 261 mg (50%) of the title compound as a solid.

[1405] The following examples and general procedures refer to intermediate
compounds and final products for general formula (VIII) identified in the
specification and in the synthesis schemes. The preparation of the
compounds of general formula (VIII) of the present invention is described
in detail using the following examples. Occasionally, the reaction may
not be applicable as described to each compound included within the
disclosed scope of the invention. The compounds for which this occurs
will be readily recognised by those skilled in the art. In these cases
the reactions can be successfully performed by conventional modifications
known to those skilled in the art, that is, by appropriate protection of
interfering groups, by changing to other conventional reagents, or by
routine modification of reaction conditions. Alternatively, other
reactions disclosed herein or otherwise conventional will be applicable
to the preparation of the corresponding compounds of the invention. In
all preparative methods, all starting materials are known or may easily
be prepared from known starting materials. The structures of the
compounds are confirmed by either elemental analysis or nuclear magnetic
resonance (NMR), where peaks assigned to characteristic protons in the
title compounds are presented where appropriate. .sup.1H NMR shifts (6H)
are given in parts per million (ppm) down field from tetramethylsilane as
internal reference standard. M.p.: is melting point and is given in
.degree. C. and is not corrected. Column chromatography was carried out
using the technique described by W. C. Still et al., J. Org. Chem. 43:
2923 (1978) on Merck silica gel 60 (Art. 9385). HPLC analyses are
performed using 5 .mu.m C18 4.times.250 mm column eluted with various
mixtures of water and acetonitrile, flow=1 ml/min, as described in the
experimental section.

[1406] The abbreviations as used in the examples have the following
meaning:

TLC: thin layer chromatography

CDCl.sub.3: deuterio chloroform

CD.sub.3OD: tetradeuterio methanol

DMSO-d.sub.6: hexadeuterio dimethylsulfoxide

DMSO: dimethylsulfoxide

THF: tetrahydrofuran

DMF: N,N-dimethylformamide

HOBT: 1-hydroxy-benzotriazole

EDAC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride

min: minutes

hrs: hours

[1407] The compounds of the invention are prepared as illustrated in the
following reaction scheme 1: General Method:

[1408] By allowing a 2-halo-3-oxo-propionic acid ester (I) wherein Y is
halo, R.sup.1 is C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl and
R.sup.2 is as defined above to react with an amide (II), wherein R.sup.3
is as defined above and X is O or S, in a solvent such as ethanol and the
like affording an thiazole, oxazol or imidazol carboxylic acid ester
(III), wherein R.sup.2 and R.sup.3 is as defined above. The thiazole,
oxazol or imidazol carboxylic acid ester (III) is hydrolysed with base
affording thiazole, oxazol or imidazol carboxylic acid (V), wherein
R.sup.2 and R.sup.3 are as defined above. The thiazole, oxazol or
imidazol carboxylic acid (V) can also be obtained from the corresponding
bromo or iodo substituted thiazole, oxazol or imidazol (IV) via halogen
lithium exchange followed by reaction with carbon dioxide in a solvent
such as THF. The thiazole, oxazol or imidazol carboxylic acid (V) is
coupled with an amine (VI), wherein R.sup.5 and R.sup.6 are as defined
above, under standard amide forming conditions (e.g. HOBT, EDAC and DIPEA
in dry THF) affording thiazole, oxazol or imidazol (VII), wherein
R.sup.2, R.sup.3, R.sup.5 and R.sup.6 are as defined above.